Pharmaceutically acceptable salt or co-crystal of 1-oxo-1,2-dihydrophthalazine compound, crystalline form thereof and preparation method therefor

Abstract

The present disclosure relates to a pharmaceutically acceptable salt or co-crystal of a 1-oxo-1,2-dihydrophthalazine compound, a crystalline form thereof, and a preparation method therefor. Specifically provided in the present disclosure are a pharmaceutically acceptable salt or co-crystal of (M)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutan[e][1,4]dioxan-4-carbonitrile, a crystal form thereof, and a preparation method therefor. The corresponding salt exhibits good stability and can be better used in clinical treatment.

Description

A pharmaceutically acceptable salt or eutectic of a 1-oxo-1,2-dihydrophthalazine compound, its crystalline form and preparation method Technical Field

[0001] This disclosure belongs to the field of pharmaceutical technology and relates to a pharmaceutically acceptable salt or eutectic of a 1-oxo-1,2-dihydrophthalazine compound, its crystalline form and preparation method. Background Technology

[0002] Protein methylarginine transferase 5 (PRMT5), an important type II arginine methyltransferase, regulates various physiological functions in mammalian cells by symmetrically dimethylating arginine residues on histones and non-histone proteins. These functions include genomic epigenetic modification, regulation of RNA splicing, DNA repair, regulation of Treg cell gene expression, and antigen presentation methylation. Studies have shown that PRMT5 overexpression plays a crucial role in proliferative diseases, metabolic diseases, hematological diseases, and various cancers.

[0003] PCT / CN2024 / 110882 provides a PRMT5 inhibitor with the chemical name (M)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutan[e][1,4]dioxane-4-carboxynitrile, having the structure shown in Formula 1.

[0004] Salt formation or eutectic formation can improve certain undesirable physicochemical or biological properties of drugs. Developing salts with superior physicochemical or pharmaceutical properties compared to (M)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutan[e][1,4]dioxane-4-carboxynitrile is of great significance. Given the importance of solid drug crystal forms and their stability to clinical treatment, in-depth research on the pharmaceutically acceptable salts and polymorphs of compound (M)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carboxynitrile and its cocrystallization is of great significance for developing drugs suitable for industrial production and with good biological activity. Summary of the Invention

[0005] This disclosure provides a pharmaceutically acceptable salt of compound (M)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutan[e][1,4]dioxahexane-4-carboxynitrile, wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, phosphate, tartrate, maleate, p-toluenesulfonate, fumarate, succinate, benzoate, hippurate, mandelate, acetate, malate, citrate, hydrobromide, and methanesulfonate.

[0006] This disclosure also provides a method for preparing a pharmaceutically acceptable salt of a compound of formula 1, comprising the step of reacting the compound of formula 1 with an acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, maleic acid, p-toluenesulfonic acid, fumaric acid, succinic acid, benzoic acid, hippuric acid, mandelic acid, acetic acid, malic acid, citric acid, hydrobromic acid, and methanesulfonic acid.

[0007] The solvents used in the salt formation of this disclosure are selected from, but not limited to, ethyl acetate, ethanol, acetone, tetrahydrofuran, methanol, isopropyl ether, methanol / isopropyl ether, isopropanol, isopropyl acetate, acetonitrile, n-heptane, cyclohexane, water, acetonitrile / methanol / water, water / methanol, acetonitrile / methanol, DMSO, dichloromethane / methyl tert-butyl ether, dichloromethane / isopropyl ether, dichloromethane / n-heptane, water / isopropanol / methyl tert-butyl ether, isopropanol, n-propanol, methyl tert-butyl ether, methyl isobutyl ketone, water / isopropanol, ethyl acetate / n-... Heptane, tetrahydrofuran / ethanol, 1,4-dioxane, water / isopropanol / n-heptane, 2-butanone, propylene glycol methyl ether, acetone / methyl tert-butyl ether, acetone / n-heptane, acetone / methyl tert-butyl ether, methanol / acetonitrile / n-heptane, methanol / acetonitrile / methyl tert-butyl ether, acetone / water, acetonitrile / water, and ethanol / dichloromethane; in some embodiments, the solvent used for salt formation is selected from ethyl acetate, ethanol, acetone, tetrahydrofuran, methanol, isopropyl ether, methanol / isopropyl ether, isopropanol, isopropyl acetate, and acetonitrile.

[0008] Furthermore, in some embodiments, the method for preparing the pharmaceutical salt and eutectic of the aforementioned compound of formula 1, or its crystal form, also includes steps such as crystallization, centrifugation (filtration), washing, or drying.

[0009] In some embodiments, the chemical ratio of the compound of Formula 1 to the acid is 3:1 to 1:3; in some embodiments, the chemical ratio of the compound of Formula 1 to the acid is 2:1 to 1:2; in some embodiments, the chemical ratio of the compound of Formula 1 to the acid includes, but is not limited to, 3:1, 2.5:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5 and 1:3; in some embodiments, the chemical ratio of the compound of Formula 1 to the acid includes, but is not limited to, 2:1, 1:1 and 1:2; in some embodiments, the chemical ratio of the compound of Formula 1 to the acid is 1:1 or 1:2.

[0010] In some embodiments, the chemical ratio of compound 1 to hydrochloric acid is 1:1.

[0011] In some implementations, the chemical ratio of the compound of Formula 1 to sulfuric acid is 1:1.

[0012] In some implementations, the chemical ratio of the compound of Formula 1 to sulfuric acid is 1:2.

[0013] In some implementations, the chemical ratio of compound 1 to phosphoric acid is 1:1.

[0014] In some implementations, the chemical ratio of compound 1 to phosphoric acid is 1:2.

[0015] In some implementations, the chemical ratio of compound 1 to phosphoric acid is 2:1.

[0016] In some embodiments, the chemical ratio of compound 1 to tartaric acid is 1:1.

[0017] In some implementations, the chemical ratio of compound 1 to maleic acid is 1:1.

[0018] In some embodiments, the chemical ratio of compound of formula 1 to p-toluenesulfonic acid is 1:1.

[0019] In some embodiments, the chemical ratio of compound of formula 1 to fumaric acid is 1:1.

[0020] In some embodiments, the chemical ratio of compound 1 to succinic acid is 1:1.

[0021] In some embodiments, the chemical ratio of compound of formula 1 to succinic acid is 1:1.5.

[0022] In some embodiments, the chemical ratio of compound of formula 1 to succinic acid is 1:2.

[0023] In some embodiments, the chemical ratio of compound 1 to benzoic acid is 1:1.

[0024] In some implementations, the chemical ratio of compound 1 to hippuric acid is 1:1.

[0025] In some embodiments, the chemical ratio of compound of formula 1 to mandelic acid is 1:1.

[0026] In some embodiments, the chemical ratio of compound 1 to acetic acid is 1:1.

[0027] In some embodiments, the chemical ratio of compound 1 to malic acid is 1:1.

[0028] In some embodiments, the chemical ratio of compound 1 to citric acid is 1:1.

[0029] In some embodiments, the chemical ratio of compound of formula 1 to citric acid is 1:0.5.

[0030] In some embodiments, the chemical ratio of compound 1 to hydrobromic acid is 1:1.

[0031] In some embodiments, the chemical ratio of compound 1 to methanesulfonic acid is 1:1.

[0032] The hydrochloride crystal form I of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 14.610, 20.080, 21.271, 22.324 and 24.621 in the X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0033] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystal form I of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 5.340, 14.610, 16.272, 20.080, 21.271, 22.324, 23.480, 24.621, and 25.346.

[0034] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystal form I of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 5.340, 10.302, 11.290, 14.610, 16.272, 20.080, 21.271, 22.324, 23.480, 24.621, 25.346, 27.371, and 29.417.

[0035] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystal form I of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 2.

[0036] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystal form I of compound 1, expressed in terms of diffraction angle 2θ, is shown in Figure 2.

[0037] This disclosure also provides a method for preparing the hydrochloride crystal form I of compound formula 1, the method comprising: adding the compound of formula 1 to solvent I, adding hydrochloric acid ethanol solution, and stirring, wherein solvent I is selected from ethyl acetate, ethanol, acetone, and tetrahydrofuran. Another aspect of this disclosure provides the sulfate crystal form I of the compound of formula 1, whose X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 5.941, 7.163, 14.633, 24.011, and 26.522.

[0038] In some embodiments, the sulfate crystal form I of the compound shown in Formula 1 has characteristic peaks at 5.941, 7.163, 12.016, 14.633, 15.622, 18.361, 19.475, 24.011 and 26.522 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0039] In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form I of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 5.941, 7.163, 12.016, 14.633, 15.622, 17.998, 18.361, 19.475, 22.769, 24.011, 26.522, and 27.361.

[0040] In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form I of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 3.

[0041] In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form I of compound 1, expressed as a diffraction angle 2θ, is shown in Figure 3.

[0042] This disclosure also provides a method for preparing sulfate crystal form I of compound of formula 1, the method comprising: adding compound of formula 1 to solvent II, adding an aqueous sulfuric acid solution, and stirring, wherein solvent II is selected from acetone, tetrahydrofuran and ethyl acetate.

[0043] The sulfate crystal form Ⅱ of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 5.952, 16.549, 19.003, 22.694 and 24.584 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0044] In some embodiments, the sulfate crystal form Ⅱ of the compound shown in Formula 1 has characteristic peaks at 5.952, 8.063, 10.135, 16.549, 19.003, 20.881, 22.694, 24.584 and 25.961 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0045] In some embodiments, the sulfate crystal form Ⅱ of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 5.952, 8.063, 10.135, 14.597, 16.549, 19.003, 19.825, 20.881, 22.694, 24.584, 25.961, and 27.256.

[0046] In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form Ⅱ of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 4.

[0047] In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form Ⅱ of compound 1, expressed in terms of diffraction angle 2θ, is shown in Figure 4.

[0048] This disclosure also provides a method for preparing sulfate crystal form Ⅱ of the compound of formula 1, the method comprising: adding the compound of formula 1 to ethyl acetate, adding an aqueous sulfuric acid solution, and stirring. Another aspect of this disclosure provides the sulfate crystal form Ⅱ of the compound of formula 1, whose X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 5.321, 15.107, 18.754, 20.155, 23.589, and 24.174.

[0049] In some embodiments, the sulfate crystal form III of the compound shown in Formula 1 has characteristic peaks at 5.321, 9.253, 14.209, 15.107, 18.754, 20.155, 21.573, 23.589, 24.174 and 27.644 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0050] In some embodiments, the sulfate crystal form IⅠI of the compound shown in Formula 1 has characteristic peaks at 5.321, 9.253, 14.209, 15.107, 16.132, 16.948, 17.853, 18.754, 20.155, 21.573, 23.589, 24.174, 27.644, and 28.733 in its X-ray powder diffraction pattern, expressed as a diffraction angle 2θ.

[0051] In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form III of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 5.

[0052] In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form III of compound 1, expressed as a diffraction angle 2θ, is shown in Figure 5.

[0053] This disclosure also provides a method for preparing sulfate crystal form III of compound of formula 1, the method comprising: adding compound of formula 1 to ethanol, adding aqueous sulfuric acid solution, and stirring. Another aspect of this disclosure provides an X-ray powder diffraction pattern of phosphate crystal form I of the compound of formula 1, expressed as a diffraction angle 2θ, with characteristic peaks at 5.837, 13.446, 16.145, 17.904, and 23.563.

[0054] In some embodiments, the phosphate crystal form I of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 5.837, 13.446, 16.145, 17.904, 22.033, 23.563, 24.452 and 26.205.

[0055] In some embodiments, the X-ray powder diffraction pattern of the phosphate crystal form I of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 5.837, 12.885, 13.446, 14.182, 15.759, 16.145, 17.904, 20.526, 22.033, 23.563, 24.452, and 26.205.

[0056] In some embodiments, the X-ray powder diffraction pattern of the phosphate crystal form I of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 6.

[0057] In some embodiments, the X-ray powder diffraction pattern of the phosphate crystal form I of compound 1, expressed in terms of diffraction angle 2θ, is shown in Figure 6.

[0058] This disclosure also provides a method for preparing phosphate crystal form I of compound of formula 1, the method comprising: adding compound of formula 1 to ethyl acetate, adding phosphate ethanol solution, and stirring.

[0059] The phosphate crystal form II of the compound of Formula 1 provided in another aspect of this disclosure has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.747, 11.567, 17.410, 22.588, 27.132 and 27.689.

[0060] In some embodiments, the phosphate crystal form II of the compound shown in Formula 1 has characteristic peaks at 5.747, 11.567, 14.202, 17.410, 20.490, 22.588, 23.400, 27.132 and 27.689 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0061] In some embodiments, the phosphate crystal form II of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 5.747, 7.118, 11.567, 14.202, 16.881, 17.410, 18.423, 18.809, 20.490, 22.588, 23.400, 27.132, and 27.689.

[0062] In some embodiments, the X-ray powder diffraction pattern of the phosphate crystal form II of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 7.

[0063] In some embodiments, the X-ray powder diffraction pattern of the phosphate crystal form II of compound 1, expressed in terms of diffraction angle 2θ, is shown in Figure 7.

[0064] This disclosure also provides a method for preparing phosphate crystal form II of compound of formula 1, the method comprising: adding compound of formula 1 to ethanol, adding phosphate ethanol solution, and stirring.

[0065] The phosphate crystal form III of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 6.037, 11.820, 15.494, 17.665 and 19.625 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0066] In some embodiments, the phosphate crystal form III of the compound shown in Formula 1 has characteristic peaks at 6.037, 11.820, 15.494, 17.665, 19.625, 19.973, 23.230 and 27.435 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0067] In some embodiments, the phosphate crystal form III of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 6.037, 11.820, 12.796, 13.205, 15.494, 15.971, 17.665, 19.625, 19.973, 21.489, 22.819, 23.230, and 27.435.

[0068] In some embodiments, the X-ray powder diffraction pattern of the phosphate crystal form III of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 8.

[0069] In some embodiments, the X-ray powder diffraction pattern of the phosphate crystal form III of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 8.

[0070] This disclosure also provides a method for preparing phosphate crystal form III of compound of formula 1, the method comprising: adding compound of formula 1 to ethanol, adding phosphate ethanol solution, and stirring.

[0071] The tartrate crystal form I of the compound of Formula 1 provided in another aspect of this disclosure has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 6.236, 10.158, 13.189, 14.998 and 15.792.

[0072] In some embodiments, the tartrate crystal form I of the compound shown in Formula 1 has characteristic peaks at 6.236, 7.241, 10.158, 13.189, 14.998, 15.792, 21.670 and 25.118 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0073] In some embodiments, the X-ray powder diffraction pattern of the tartrate crystal form I of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 6.236, 7.241, 10.158, 13.189, 14.147, 14.998, 15.792, 19.159, 20.561, 21.670, and 25.118.

[0074] In some embodiments, the X-ray powder diffraction pattern of the tartrate crystal form I of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the characteristic peak positions as shown in Table 9.

[0075] In some embodiments, the X-ray powder diffraction pattern of the tartrate crystal form I of compound 1, expressed in terms of diffraction angle 2θ, is shown in Figure 9.

[0076] This disclosure also provides a method for preparing tartrate crystal form I of compound of formula 1, the method comprising: adding compound of formula 1 to solvent II, adding tartrate ethanol solution, and stirring, wherein solvent II is selected from acetone, tetrahydrofuran and ethyl acetate.

[0077] The maleate crystal form I of the compound of Formula 1 provided in another aspect of this disclosure has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 7.549, 14.615, 15.377, 24.328 and 24.608.

[0078] In some embodiments, the maleate crystal form I of the compound shown in Formula 1 has characteristic peaks at 6.229, 7.549, 14.615, 15.377, 21.796, 24.328, 24.608 and 27.427 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0079] In some embodiments, the maleate crystal form I of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 4.917, 6.229, 7.549, 14.615, 15.377, 16.487, 16.854, 21.796, 24.328, 24.608, 25.473, and 27.427.

[0080] In some embodiments, the X-ray powder diffraction pattern of the maleate crystal form I of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, has characteristic peaks as shown in Table 10.

[0081] In some embodiments, the X-ray powder diffraction pattern of maleate crystal form I of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, is shown in Figure 10.

[0082] This disclosure also provides a method for preparing maleate crystal form I of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to ethanol, adding maleic acid, and stirring. Another aspect of this disclosure provides the maleate crystal form II of the compound shown in Formula 1, whose X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 6.293, 7.281, 14.477, 24.632, 25.056, and 25.772.

[0083] In some embodiments, the maleate crystal form II of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 6.293, 7.281, 13.945, 14.477, 14.848, 15.371, 18.612, 24.632, 25.056, and 25.772.

[0084] In some embodiments, the maleate crystal form II of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 6.293, 7.281, 9.256, 9.888, 13.945, 14.477, 14.848, 15.371, 16.315, 18.612, 20.465, 24.064, 24.632, 25.056, and 25.772.

[0085] In some embodiments, the X-ray powder diffraction pattern of the maleate crystal form II of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, has characteristic peaks as shown in Table 11.

[0086] In some embodiments, the X-ray powder diffraction pattern of maleate crystal form II of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, is shown in Figure 11.

[0087] This disclosure also provides a method for preparing maleate crystal form II of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to methanol, adding maleic acid, stirring, then adding isopropyl ether and stirring.

[0088] The maleate crystal form III of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 7.935, 14.788, 15.591, 24.341 and 26.531 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0089] In some embodiments, the maleate crystal form III of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 7.935, 14.788, 15.591, 16.091, 17.206, 17.563, 23.234, 24.341, and 26.531.

[0090] In some embodiments, the maleate crystal form III of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 7.935, 8.200, 10.415, 14.788, 15.591, 16.091, 16.661, 17.206, 17.563, 18.423, 23.234, 24.341, and 26.531.

[0091] In some embodiments, the X-ray powder diffraction pattern of the maleate crystal form III of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 12.

[0092] In some embodiments, the X-ray powder diffraction pattern of the maleate crystal form III of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 12.

[0093] This disclosure also provides a method for preparing maleate crystal form III of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to isopropanol, adding maleic acid, dissolving, and stirring.

[0094] The maleate crystal form IV of the compound of Formula 1 provided in another aspect of this disclosure has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 14.202, 16.008, 17.828, 18.738, 20.160 and 25.578.

[0095] In some embodiments, the maleate crystal form IV of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 10.800, 14.202, 16.008, 17.828, 18.738, 20.160, 21.513 and 25.578.

[0096] In some embodiments, the X-ray powder diffraction pattern of the maleate crystal form IV of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 10.800, 14.202, 16.008, 17.828, 18.738, 20.160, 21.513, 23.714, 24.502, 25.578, 26.834, 27.106, and 27.731.

[0097] In some embodiments, the X-ray powder diffraction pattern of the maleate crystal form IV of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, has the characteristic peak positions shown in Table 13.

[0098] In some embodiments, the X-ray powder diffraction pattern of maleate crystal form IV of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, is shown in Figure 13.

[0099] This disclosure also provides a method for preparing maleate crystal form IV of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to isopropyl acetate, adding maleic acid, and stirring.

[0100] The maleate crystal form V of the compound of Formula 1 provided in another aspect of this disclosure has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.725, 8.543, 14.128, 14.944, 15.703 and 17.370.

[0101] In some embodiments, the maleate crystal form V of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 5.725, 8.543, 10.642, 11.337, 14.128, 14.944, 15.703, 17.370, and 23.583.

[0102] In some embodiments, the maleate crystal form V of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 5.725, 8.543, 10.642, 11.337, 13.240, 14.128, 14.944, 15.703, 17.370, 19.948, 23.583, and 24.797.

[0103] In some embodiments, the X-ray powder diffraction pattern of the maleate crystal form V of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 14.

[0104] In some embodiments, the X-ray powder diffraction pattern of the maleate crystal form V of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 14.

[0105] This disclosure also provides a method for preparing maleate crystal form V of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to ethanol, adding maleic acid, and stirring.

[0106] The maleate crystal form VI of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 5.787, 22.216, 23.836 and 28.273 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0107] In some embodiments, the maleate crystal form VI of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 5.787, 17.584, 22.216, 23.836, 25.712, 28.089, 28.273 and 29.463.

[0108] In some embodiments, the maleate crystal form VI of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 5.787, 11.396, 17.584, 22.216, 23.369, 23.836, 25.712, 25.922, 28.089, 28.273, and 29.463.

[0109] In some embodiments, the X-ray powder diffraction pattern of the maleate crystal form VI of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, has the characteristic peak positions shown in Table 15.

[0110] In some embodiments, the X-ray powder diffraction pattern of the maleate crystal form VI of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 15.

[0111] This disclosure also provides a method for preparing maleate crystal form VI of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to acetonitrile, adding an acetonitrile solution of maleic acid, and stirring.

[0112] The p-toluenesulfonate crystal form I of the compound of Formula 1 provided in another aspect of this disclosure has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 6.435, 10.326, 12.920, 15.076, 16.033 and 16.846.

[0113] In some embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form I of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 5.419, 6.435, 9.478, 10.326, 12.920, 15.076, 16.033, 16.846, and 23.977.

[0114] In some embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form I of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 5.419, 6.435, 9.478, 10.326, 12.043, 12.920, 13.551, 15.076, 16.033, 16.846, 23.977, and 24.347.

[0115] In some embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form I of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 16.

[0116] In some embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form I of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 16.

[0117] This disclosure also provides a method for preparing p-toluenesulfonate crystal form I of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to ethyl acetate, adding a p-toluenesulfonic acid ethanol solution, and stirring.

[0118] The p-toluenesulfonate crystal form II of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 9.309, 13.551, 15.584 and 24.347 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0119] The p-toluenesulfonate crystal form II of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 9.309, 13.551, 15.584, 18.388 and 24.347 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0120] In some embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form II of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 17.

[0121] This disclosure also provides a method for preparing p-toluenesulfonate crystal form II of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to acetone, adding a p-toluenesulfonic acid ethanol solution, and stirring.

[0122] The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form III of the compound of Formula 1 provided in another aspect of this disclosure, expressed in terms of diffraction angle 2θ, has characteristic peaks at 10.767, 11.445, 15.268, 16.932 and 24.701.

[0123] In some embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form III of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 6.667, 9.471, 10.767, 11.445, 15.268, 16.932, 19.825, and 24.701.

[0124] In some embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form III of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 6.667, 9.471, 10.767, 11.445, 12.359, 14.497, 15.268, 16.932, 19.825, 24.701, and 26.660.

[0125] In some embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form III of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 18.

[0126] In some embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form III of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 18.

[0127] This disclosure also provides a method for preparing p-toluenesulfonate crystal form III of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to ethanol, adding a p-toluenesulfonic acid ethanol solution, and stirring.

[0128] The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form IV of the compound of Formula 1 provided in another aspect of this disclosure, expressed in terms of diffraction angle 2θ, has characteristic peaks at 6.092, 13.320, 17.060, 18.476, 21.283, 24.446 and 24.687.

[0129] In some embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form IV of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 6.092, 10.983, 13.320, 17.060, 18.476, 21.283, 22.196, 23.268, 24.446, 24.687, and 26.959.

[0130] In some embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form IV of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 6.092, 8.042, 10.983, 13.320, 15.351, 17.060, 18.476, 21.283, 22.196, 23.268, 24.446, 24.687, and 26.959.

[0131] In some embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form IV of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the characteristic peak positions as shown in Table 19.

[0132] In some embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form IV of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 19.

[0133] This disclosure also provides a method for preparing p-toluenesulfonate crystal form IV of the compound of Formula 1, the method comprising: heating p-toluenesulfonate crystal form III of the compound of Formula 1 to 260°C.

[0134] The fumarate crystal form I of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 4.760, 14.588 and 19.450 in the X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0135] The fumarate crystal form I of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 4.760, 11.938, 14.588, 19.450 and 21.705 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0136] In some embodiments, the fumarate crystal form I of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 4.760, 9.204, 11.938, 14.588, 18.143, 19.450, 21.705, 25.258, and 28.413.

[0137] In some embodiments, the X-ray powder diffraction pattern of the fumarate crystal form I of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 20.

[0138] This disclosure also provides a method for preparing fumarate crystal form I of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to solvent III, adding fumaric acid, and stirring, wherein solvent III is selected from ethanol, acetone and tetrahydrofuran.

[0139] The succinate crystal form I of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 5.568, 7.192, 14.899, 21.131 and 26.019 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0140] In some embodiments, the succinate crystal form I of the compound shown in Formula 1 has characteristic peaks at 5.568, 7.192, 11.209, 12.464, 14.899, 16.180, 21.131, 23.340 and 26.019 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0141] In some embodiments, the succinate crystal form I of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 5.568, 7.192, 11.209, 12.464, 14.899, 15.724, 16.180, 18.037, 21.131, 23.340, 24.312, and 26.019.

[0142] In some embodiments, the X-ray powder diffraction pattern of the succinate crystal form I of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 21.

[0143] In some embodiments, the X-ray powder diffraction pattern of the succinate crystal form I of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 21.

[0144] This disclosure also provides a method for preparing succinate crystal form I of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to ethyl acetate, adding succinic acid, and stirring.

[0145] The succinate crystal form II of the compound of Formula 1 provided in another aspect of this disclosure has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.208, 16.004, 21.928, 22.454, 25.121 and 33.110.

[0146] In some embodiments, the succinate crystal form II of the compound shown in Formula 1 has characteristic peaks at 5.208, 16.004, 18.563, 21.928, 22.454, 25.121, 26.835 and 33.110 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0147] In some embodiments, the succinate form II of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 5.208, 16.004, 18.563, 20.456, 21.928, 22.454, 25.121, 26.835, 32.198, and 33.110.

[0148] In some embodiments, the X-ray powder diffraction pattern of the succinate form II of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 22.

[0149] This disclosure also provides a method for preparing succinate crystal form II of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to tetrahydrofuran or acetone, adding succinic acid, and stirring.

[0150] The benzoate crystal form I of the compound of Formula 1 provided in another aspect of this disclosure has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.676, 11.524, 16.837, 17.189 and 23.016.

[0151] In some embodiments, the benzoate crystal form I of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 5.676, 11.524, 16.837, 17.189, 19.104, 20.647, 22.585, 23.016, and 27.186.

[0152] In some embodiments, the benzoate crystal form I of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 5.676, 8.921, 11.524, 13.931, 16.837, 17.189, 18.429, 19.104, 20.647, 22.585, 23.016, 27.186, and 27.909.

[0153] In some embodiments, the X-ray powder diffraction pattern of the benzoate crystal form I of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 23.

[0154] In some embodiments, the X-ray powder diffraction pattern of the benzoate crystal form I of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 23.

[0155] This disclosure also provides a method for preparing benzoate crystal form I of the compound of Formula 1, the method comprising: adding the compound of Formula 1 to ethanol, adding a benzoic acid ethanol solution, and stirring. Another aspect of this disclosure provides an X-ray powder diffraction pattern of benzoate crystal form II of the compound of Formula 1, expressed as a diffraction angle 2θ, which shows characteristic peaks at 6.294, 7.577, 12.681, and 13.528.

[0156] In some embodiments, the benzoate crystal form II of the compound shown in Formula 1 has characteristic peaks at 6.294, 7.577, 8.433, 12.681, 13.528, 17.757, 21.545 and 23.195 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0157] In some embodiments, the benzoate crystal form II of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 6.294, 7.577, 8.433, 11.237, 12.681, 13.528, 14.707, 17.757, 18.318, 19.229, 21.545, and 23.195.

[0158] In some embodiments, the X-ray powder diffraction pattern of the benzoate form II of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 24.

[0159] In some embodiments, the X-ray powder diffraction pattern of the benzoate form II of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 24.

[0160] This disclosure also provides a method for preparing benzoate crystal form II of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to tetrahydrofuran, adding an ethanol solution of benzoic acid, and stirring.

[0161] In some embodiments, the benzoate crystal form III of the compound shown in Formula 1 has characteristic peaks at 5.961, 9.643, 10.730, 12.052, 18.228 and 21.679 in its X-ray powder diffraction pattern, expressed as a diffraction angle 2θ.

[0162] In some embodiments, the benzoate crystal form III of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 5.369, 5.961, 9.643, 10.730, 12.052, 14.462, 18.228, 19.645, and 21.679.

[0163] In some embodiments, the benzoate crystal form III of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 5.369, 5.961, 9.643, 10.730, 12.052, 14.462, 18.228, 19.645, 21.679, 24.395, 24.964, and 27.293.

[0164] In some embodiments, the X-ray powder diffraction pattern of the benzoate crystal form III of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 25.

[0165] In some embodiments, the X-ray powder diffraction pattern of the benzoate form III of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 25.

[0166] This disclosure also provides a method for preparing benzoate crystal form III of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to ethanol, adding a benzoic acid ethanol solution, and stirring.

[0167] In some embodiments, the benzoate crystal form IV of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 6.180, 13.025, 14.497, 17.687, 18.107, and 23.054.

[0168] In some embodiments, the benzoate crystal form IV of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 6.180, 13.025, 14.497, 17.687, 18.107, 18.738, 19.354, 22.154, 23.054, and 23.646.

[0169] In some embodiments, the X-ray powder diffraction pattern of the benzoate form IV of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 26.

[0170] In some embodiments, the X-ray powder diffraction pattern of the benzoate form IV of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 26.

[0171] This disclosure also provides a method for preparing benzoate crystal form IV of the compound shown in Formula 1, the method comprising:

[0172] Method 1: Heat the benzoate crystal form I of compound 1 to 190℃;

[0173] Method 2: Heat the benzoate crystal form II of compound 1 to 170°C;

[0174] Method 3: Heating the benzoate crystal form II of compound 1 to 195°C.

[0175] In some embodiments, the hippurate crystal form I of the compound shown in Formula 1 has characteristic peaks at 4.526, 11.532, 13.672 and 15.636 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0176] In some embodiments, the hippurate crystal form I of the compound shown in Formula 1 has characteristic peaks at 4.526, 11.532, 13.672, 15.636, 18.204, 20.207 and 22.619 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0177] In some embodiments, the X-ray powder diffraction pattern of the hippurate crystal form I of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 4.526, 11.532, 12.879, 13.672, 15.636, 17.784, 18.204, 20.207, 22.619, 23.179, 24.966, and 27.033.

[0178] In some embodiments, the X-ray powder diffraction pattern of the hippurate crystal form I of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 27.

[0179] In some embodiments, the X-ray powder diffraction pattern of the hippurate crystal form I of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 27.

[0180] This disclosure also provides a method for preparing hippurate crystal form I of the compound shown in Formula 1, the method comprising:

[0181] The compound of Formula 1 was added to solvent IV, hippuric acid was added, and the mixture was stirred. Solvent IV was selected from ethanol, acetonitrile, and ethyl acetate.

[0182] The hippurate crystal form II of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 11.641, 15.315, 17.299, 17.598 and 18.774 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0183] In some embodiments, the hippurate crystal form II of the compound shown in Formula 1 has characteristic peaks at 11.641, 13.134, 13.758, 15.315, 17.299, 17.598, 18.774 and 26.308 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0184] In some embodiments, the hippurate crystal form II of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 11.641, 12.362, 13.134, 13.758, 15.315, 17.299, 17.598, 18.774, 23.666, 25.624, and 26.308.

[0185] In some embodiments, the X-ray powder diffraction pattern of the hippurate crystal form II of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 28.

[0186] In some embodiments, the X-ray powder diffraction pattern of the hippurate crystal form II of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 28.

[0187] This disclosure also provides a method for preparing hippurate crystal form II of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to acetonitrile, adding an acetonitrile solution of hippuric acid, and stirring.

[0188] The mandelate crystal form I of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 5.699, 7.545, 8.540, 15.955 and 17.460 in the X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0189] In some embodiments, the amylopectin crystal form I of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 5.699, 7.545, 8.540, 14.338, 15.216, 15.955, 17.460, 17.977 and 23.061.

[0190] In some embodiments, the X-ray powder diffraction pattern of the mandelate crystal form I of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 5.699, 7.545, 8.540, 14.338, 15.216, 15.955, 17.460, 17.977, 19.964, 21.348, 23.061, 23.389, 25.135, and 25.655.

[0191] In some embodiments, the X-ray powder diffraction pattern of the mandelate crystal form I of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 29.

[0192] In some embodiments, the X-ray powder diffraction pattern of the mandelate crystal form I of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 29.

[0193] This disclosure also provides a method for preparing mandelic acid salt crystal form I of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to solvent IV, adding S-mandelic acid, and stirring, wherein solvent IV is selected from ethanol, acetonitrile and ethyl acetate.

[0194] The acetate crystal form I of the compound of Formula 1 provided in another aspect of this disclosure has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.867, 6.617 and 15.128.

[0195] In some embodiments, the X-ray powder diffraction pattern of the acetate crystal form I of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 5.867, 6.617, 9.309, 10.957, and 15.128.

[0196] In some embodiments, the X-ray powder diffraction pattern of the acetate crystal form I of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 5.867, 6.617, 9.309, 10.957, 12.394, and 15.128.

[0197] In some embodiments, the X-ray powder diffraction pattern of the acetate crystal form I of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 30.

[0198] In some embodiments, the X-ray powder diffraction pattern of the acetate crystal form I of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 30.

[0199] This disclosure also provides a method for preparing the acetate crystal form I of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to ethyl acetate, adding an acetic acid-ethanol solution, and stirring.

[0200] The malate crystal form I of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 5.258, 10.996, 13.809 and 16.252 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0201] In some embodiments, the malate crystal form I of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 5.258, 10.996, 12.513, 12.958, 13.809, and 16.252.

[0202] In some embodiments, the malate crystal form I of the compound shown in Formula 1 has characteristic peaks at 5.258, 10.996, 12.513, 12.958, 13.809, 16.252 and 21.953 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0203] In some embodiments, the X-ray powder diffraction pattern of the malate crystal form I of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 31.

[0204] This disclosure also provides a method for preparing the malate crystal form I of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to tetrahydrofuran, adding a malic acid ethanol solution, and stirring.

[0205] The citrate crystal form I of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 9.278, 9.676, 15.361, 16.466 and 24.077 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0206] In some embodiments, the citrate I crystal form of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 9.278, 9.676, 14.448, 15.361, 16.466, 19.471, 24.077, and 25.689.

[0207] In some embodiments, the citrate crystal form I of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 9.278, 9.676, 14.448, 15.361, 15.931, 16.466, 17.725, 19.471, 24.077, and 25.689.

[0208] In some embodiments, the citrate crystal form I of the compound shown in Formula 1, with the characteristic peak positions of its X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, is shown in Table 32.

[0209] In some embodiments, the X-ray powder diffraction pattern of the citrate crystal form I of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 32.

[0210] This disclosure also provides a method for preparing citrate crystal form I of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to ethanol, adding an ethanol solution of citric acid, and stirring.

[0211] The hydrobromide crystal form I of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 5.336, 21.301 and 24.445 in the X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0212] The hydrobromide crystal form I of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 5.336, 21.301, 22.149, 23.383 and 24.445 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0213] In some embodiments, the hydrobromide crystal form I of the compound shown in Formula 1 has characteristic peaks at 5.336, 19.857, 21.301, 22.149, 23.383, 24.445 and 29.264 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0214] In some embodiments, the X-ray powder diffraction pattern of the hydrobromide crystal form I of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of the characteristic peaks as shown in Table 33.

[0215] In some embodiments, the X-ray powder diffraction pattern of the hydrobromide crystal form I of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 33.

[0216] This disclosure also provides a method for preparing hydrobromide crystal form I of the compound shown in Formula 1, the method comprising: adding the compound of Formula 1 to ethanol, adding 40% hydrobromic acid, dissolving, and stirring.

[0217] The hydrochloride crystal form II of the compound of Formula 1 provided in another aspect of this disclosure has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, which has characteristic peaks at at least one (e.g., at position 1, 2, 3, or 4) selected from 8.0°±0.2°, 14.3°±0.2°, 16.4°±0.2°, and 16.5°±0.2°.

[0218] The hydrochloride crystal form II of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 8.0°±0.2°, 14.3°±0.2°, 16.4°±0.2°, and 16.5°±0.2° in X-ray powder diffraction pattern expressed as diffraction angle 2θ.

[0219] The hydrochloride crystal form II of the compound of Formula 1 provided in another aspect of this disclosure has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, which has characteristic peaks at at least one of the following angles (e.g., 1, 2, 3, 4, 5, 6, 7, 8): 8.

[0220] The hydrochloride crystal form II of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 8.0°±0.2°, 14.3°±0.2°, 16.4°±0.2°, 16.5°±0.2°, 23.5°±0.2°, 23.9°±0.2°, 31.7°±0.2°, and 31.8°±0.2° in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0221] The hydrochloride crystal form II of the compound of Formula 1 provided in another aspect of this disclosure has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, which has characteristic peaks at at least one of the following angles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14): 5.0°±0.2°, 8.0°±0.2°, 14.3°±0.2°, 16.4°±0.2°, 16.5°±0.2°, 23.5°±0.2°, 23.9°±0.2°, 24.3°±0.2°, 24.8°±0.2°, 26.1°±0.2°, 27.3°±0.2°, 27.4°±0.2°, 31.7°±0.2°, 31.8°±0.2°.

[0222] The hydrochloride crystal form II of the compound of Formula 1 provided in another aspect of this disclosure has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.0°±0.2°, 8.0°±0.2°, 14.3°±0.2°, 16.4°±0.2°, 16.5°±0.2°, 23.5°±0.2°, 23.9°±0.2°, 24.3°±0.2°, 24.8°±0.2°, 26.1°±0.2°, 27.3°±0.2°, 27.4°±0.2°, 31.7°±0.2°, and 31.8°±0.2°.

[0223] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystal form II of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 37.

[0224] This disclosure also provides a method for preparing hydrochloride crystal form II of compound of formula 1, the method comprising: adding compound of formula 1 to an aqueous hydrochloric acid solution and stirring.

[0225] The hydrochloride crystal form III of the compound of Formula 1 provided in another aspect of this disclosure has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, which has characteristic peaks at at least one (e.g., at position 1, 2, 3, or 4) selected from 15.2°±0.2°, 16.1°±0.2°, 16.5°±0.2°, and 23.2°±0.2°.

[0226] The hydrochloride crystal form III of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 15.2°±0.2°, 16.1°±0.2°, 16.5°±0.2°, and 23.2°±0.2° in X-ray powder diffraction pattern expressed as diffraction angle 2θ.

[0227] The hydrochloride crystal form III of the compound of Formula 1 provided in another aspect of this disclosure has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, which has characteristic peaks at at least one of the following angles (e.g., 1, 2, 3, 4, 5, 6, 7, 8): 9.7°±0.2°, 10.0°±0.2°, 14.2°±0.2°, 14.4°±0.2°, 15.2°±0.2°, 16.1°±0.2°, 16.5°±0.2°, and 23.2°±0.2°.

[0228] The hydrochloride crystal form III of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 9.7°±0.2°, 10.0°±0.2°, 14.2°±0.2°, 14.4°±0.2°, 15.2°±0.2°, 16.1°±0.2°, 16.5°±0.2°, and 23.2°±0.2°, as expressed in diffraction angle 2θ.

[0229] The hydrochloride crystal form III of the compound of Formula 1 provided in another aspect of this disclosure has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, which has characteristic peaks at at least one of the following angles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12): 9.7°±0.2°, 10.0°±0.2°, 12.5°±0.2°, 13.0°±0.2°, 14.2°±0.2°, 14.4°±0.2°, 15.2°±0.2°, 16.1°±0.2°, 16.5°±0.2°, 23.2°±0.2°, 25.7°±0.2°, and 26.0°±0.2°.

[0230] The hydrochloride crystal form III of the compound of Formula 1 provided in another aspect of this disclosure has a characteristic peak at 9.7°±0.2°, 10.0°±0.2°, 12.5°±0.2°, 13.0°±0.2°, 14.2°±0.2°, 14.4°±0.2°, 15.2°±0.2°, 16.1°±0.2°, 16.5°±0.2°, 23.2°±0.2°, 25.7°±0.2°, and 26.0°±0.2° in its X-ray powder diffraction pattern, expressed as a diffraction angle 2θ.

[0231] The X-ray powder diffraction pattern of the hydrochloride crystal form III of the compound of Formula 1, provided in another aspect of this disclosure, expressed as a diffraction angle 2θ, is shown in the range of 5.7°±0.2°, 9.7°±0.2°, 10.0°±0.2°, 11.3°±0.2°, 12.5°±0.2°, 13.0°±0.2°, 13.1°±0.2°, 14.2°±0.2°, and 14.4°±0.2°. At least one of the following (e.g., positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17) has a characteristic peak: °, 15.2°±0.2°, 16.1°±0.2°, 16.5°±0.2°, 17.5°±0.2°, 19.6°±0.2°, 23.2°±0.2°, 25.7°±0.2°, or 26.0°±0.2°.

[0232] The hydrochloride crystal form III of the compound of Formula 1 provided in another aspect of this disclosure has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 5.7°±0.2°, 9.7°±0.2°, 10.0°±0.2°, 11.3°±0.2°, 12.5°±0.2°, 13.0°±0.2°, 13.1°±0.2°, 14.2°±0.2°, 14.4°±0.2°, 15.2°±0.2°, 16.1°±0.2°, 16.5°±0.2°, 17.5°±0.2°, 19.6°±0.2°, 23.2°±0.2°, 25.7°±0.2°, and 26.0°±0.2°.

[0233] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystal form III of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is shown in Figure 38.

[0234] This disclosure also provides a method for preparing the hydrochloride crystal form III of compound of formula 1, the method comprising: adding compound of formula 1 to an aqueous hydrochloric acid solution, stirring, and drying.

[0235] In some embodiments, the hydrochloric acid-ethanol solution is a 2M hydrochloric acid-ethanol solution;

[0236] In some embodiments, the sulfuric acid aqueous solution is a 2M sulfuric acid aqueous solution;

[0237] In some embodiments, the phosphate ethanol solution is a 2M phosphate ethanol solution;

[0238] In some embodiments, the tartaric acid ethanol solution is a 2M tartaric acid ethanol solution;

[0239] In some embodiments, the p-toluenesulfonic acid ethanol solution is a 2M p-toluenesulfonic acid ethanol solution;

[0240] In some embodiments, the benzoic acid ethanol solution is a 2M benzoic acid ethanol solution;

[0241] In some embodiments, the acetic acid-ethanol solution is a 2M acetic acid-ethanol solution;

[0242] In some embodiments, the malic acid ethanol solution is a 2M malic acid ethanol solution;

[0243] In some embodiments, the citric acid ethanol solution is a 2M citric acid ethanol solution;

[0244] In some embodiments, the hydrochloric acid aqueous solution has a pH of 1.6. This disclosure provides a cocrystal of the compound of Formula 1, wherein the ligands of the cocrystal are selected from saccharin, L-phenylalanine, L-tyrosine, L-tryptophan, L-histidine, L-aspartic acid, L-arginine, L-lysine, and L-proline.

[0245] This disclosure provides a co-crystal of the compound shown in Formula 1 and saccharin.

[0246] This disclosure also provides a method for preparing a cocrystal of a compound of Formula 1, comprising the step of reacting the compound of Formula 1 with a ligand, wherein the ligand is selected from saccharin, L-phenylalanine, L-tyrosine, L-tryptophan, L-histidine, L-aspartic acid, L-arginine, L-lysine and L-proline.

[0247] This disclosure also provides a method for preparing a co-crystal of a compound of Formula 1 and saccharin, comprising the step of reacting the compound of Formula 1 with saccharin.

[0248] Furthermore, in some embodiments, the method for preparing the eutectic of the aforementioned compound of formula 1 also includes steps such as crystallization, centrifugation (filtration), washing, or drying.

[0249] Furthermore, in some embodiments, the method for preparing the co-crystal of the aforementioned Formula 1 compound and saccharin also includes steps such as crystallization, centrifugation (filtration), washing or drying.

[0250] The solvents used to form the eutectic in this disclosure are selected from, but are not limited to, ethanol, ethyl acetate, and acetonitrile.

[0251] The solvents used in the formation of saccharin eutectic in this disclosure are selected from, but are not limited to, ethanol, ethyl acetate, and acetonitrile.

[0252] In optional embodiments, the chemical ratio of the compound of Formula 1 to the ligand is 3:1 to 1:3. In some embodiments, the chemical ratio of the compound of Formula 1 to the ligand is 2:1 to 1:2. In some embodiments, the ratios include, but are not limited to, 3:1, 2:1, 1:1, 1:2 and 1:3. In some embodiments, the ratios include, but are not limited to, 1:1 or 1:2.

[0253] In optional embodiments, the chemical ratio of compound 1 to saccharin is 3:1 to 1:3. In some embodiments, the chemical ratio of compound 1 to saccharin is 2:1 to 1:2. In some embodiments, it includes, but is not limited to, 3:1, 2:1, 1:1, 1:2 and 1:3. In some embodiments, it includes, but is not limited to, 1:1 or 1:2.

[0254] In some implementations, the chemical ratio of compound 1 to saccharin is 1:1.

[0255] In some embodiments, the chemical ratio of compound 1 to saccharin is 1:2.

[0256] The saccharin eutectic A of the compound of Formula 1 provided in another aspect of this disclosure has an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, with characteristic peaks at 16.700, 17.339, 20.409, 20.747 and 24.370.

[0257] In some embodiments, the saccharin eutectic A of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 11.520, 16.700, 17.339, 20.409, 20.747, 23.313, 24.370 and 26.464.

[0258] In some embodiments, the X-ray powder diffraction pattern of the saccharin eutectic A of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 11.520, 14.798, 15.492, 16.700, 17.339, 20.409, 20.747, 23.313, 24.370, 26.464, and 28.063.

[0259] In some embodiments, the X-ray powder diffraction pattern of the saccharin eutectic A of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of its characteristic peaks as shown in Table 34.

[0260] In some embodiments, the X-ray powder diffraction pattern of the saccharin eutectic A of Formula 1, expressed as a diffraction angle 2θ, is shown in Figure 34.

[0261] This disclosure also provides a method for preparing saccharin eutectic A of compound of formula 1, the method comprising: adding the compound of formula 1 to ethanol, adding saccharin, and stirring. Another aspect of this disclosure provides a saccharin eutectic B of the compound of formula 1, whose X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 5.473, 7.271, 9.430, 15.369, and 26.417.

[0262] In some embodiments, the saccharin eutectic B of the compound shown in Formula 1, as expressed in diffraction angle 2θ, has characteristic peaks at 5.473, 7.271, 9.430, 13.446, 14.609, 15.369, 17.666 and 26.417.

[0263] In some embodiments, the X-ray powder diffraction pattern of the saccharin eutectic B of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 5.473, 7.271, 9.430, 11.011, 11.370, 13.446, 14.609, 14.946, 15.369, 17.304, 17.666, 25.472, and 26.417.

[0264] In some embodiments, the X-ray powder diffraction pattern of the saccharin eutectic B of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, shows the positions of its characteristic peaks as shown in Table 35.

[0265] In some embodiments, the X-ray powder diffraction pattern of the saccharin eutectic B of Formula 1, expressed as a diffraction angle 2θ, is shown in Figure 35.

[0266] This disclosure also provides a method for preparing saccharin eutectic B, a compound of formula 1, the method comprising:

[0267] Add the compound of formula 1 to ethyl acetate or acetonitrile, add saccharin, and stir.

[0268] The saccharin eutectic C of the compound of Formula 1 provided in another aspect of this disclosure has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, with characteristic peaks at 13.275, 18.257, 19.198, 19.725, 22.442 and 23.677.

[0269] In some embodiments, the saccharin eutectic C of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 6.471, 13.275, 16.594, 18.257, 19.198, 19.725, 22.442, 23.677, and 25.084.

[0270] In some embodiments, the X-ray powder diffraction pattern of the saccharin eutectic C of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 6.471, 8.688, 11.123, 11.463, 12.503, 13.275, 14.057, 16.594, 18.257, 19.198, 19.725, 22.442, 23.677, 25.084, and 29.628.

[0271] In some embodiments, the X-ray powder diffraction pattern of the saccharin eutectic C of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, has the characteristic peak positions shown in Table 36.

[0272] In some embodiments, the X-ray powder diffraction pattern of the saccharin eutectic C of Formula 1, expressed as a diffraction angle 2θ, is shown in Figure 36.

[0273] This disclosure also provides a method for preparing saccharin eutectic C of Formula 1, the method comprising: adding the Formula 1 compound to acetonitrile, adding saccharin, and stirring.

[0274] This disclosure also relates to the following specific implementation plans:

[0275] 1. A pharmaceutically acceptable salt of compound (M)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carboxynitrile, said pharmaceutically acceptable salt being selected from hydrochloride, sulfate, phosphate, tartrate, maleate, p-toluenesulfonate, fumarate, succinate, benzoate, hippurate, mandelate, acetate, malate, citrate, hydrobromide, and methanesulfonate.

[0276] 2. The pharmaceutically usable salt according to embodiment 1, characterized in that the chemical ratio of the compound of formula 1 to the acid is 3:1-1:3, for example 2:1-1:2, for example 1:1 or 1:2.

[0277] 3. The method for preparing a pharmaceutically acceptable salt according to embodiment 1 or 2 includes the step of reacting a compound of formula 1 with an acid, wherein the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, maleic acid, p-toluenesulfonic acid, fumaric acid, succinic acid, benzoic acid, hippuric acid, mandelic acid, acetic acid, malic acid, citric acid, hydrobromic acid, and methanesulfonic acid.

[0278] 4. A hydrochloride crystal form of the compound shown in Formula 1, characterized in that the X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 14.610, 20.080, 21.271, 22.324, and 24.621, for example, characteristic peaks at 5.340, 14.610, 16.272, 20.080, 21.271, 22.324, 23.480, 24.621, and 25.346, for example, characteristic peaks at 5.340, 10.302, 11.290, 14.610, 16.272, 20.080, 21.271, 22.324, 23.480, 24.621, 25.346, 27.371, and 29.417.

[0279] 5. The hydrochloride crystal form according to embodiment 4, characterized in that the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in Figure 2.

[0280] 6. A method for preparing the hydrochloride crystal form as described in embodiment 4 or 5, the method comprising: adding a compound of formula 1 to solvent I, adding hydrochloric acid ethanol solution, and stirring, wherein solvent I is selected from ethyl acetate, ethanol, acetone and tetrahydrofuran.

[0281] 7. A sulfate crystal form of the compound shown in Formula 1, characterized in that the X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 5.952, 16.549, 19.003, 22.694, and 24.584, for example, at 5.952, 8.063, 10.135, 16.549, 19.003, 20.881, 22.694, 24.584, and 25.961, for example, at 5.952, 8.063, 10.135, 14.597, 16.549, 19.003, 19.825, 20.881, 22.694, 24.584, 25.961, and 27.256.

[0282] 8. The sulfate crystal form according to embodiment 7, characterized in that the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in Figure 4.

[0283] 9. A method for preparing the sulfate crystal form as described in embodiment 7 or 8, the method comprising: adding the compound of formula 1 to ethyl acetate, adding an aqueous sulfuric acid solution, and stirring.

[0284] 10. A sulfate crystal form of the compound shown in Formula 1, characterized in that its X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 5.321, 15.107, 18.754, 20.155, 23.589, and 24.174, for example at 5.321, 9.253, 14.209, 15.107, 18.754, 20.155, ... Characteristic peaks are present at 21.573, 23.589, 24.174, and 27.644, and similar characteristic peaks are present at 5.321, 9.253, 14.209, 15.107, 16.132, 16.948, 17.853, 18.754, 20.155, 21.573, 23.589, 24.174, 27.644, and 28.733.

[0285] 11. The sulfate crystal form according to embodiment 10, characterized in that the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in Figure 5.

[0286] 12. A method for preparing the sulfate crystal form as described in embodiment 10 or 11, the method comprising: adding the compound of formula 1 to ethanol, adding an aqueous sulfuric acid solution, and stirring.

[0287] 13. A maleate crystal form of the compound shown in Formula 1, characterized in that the X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 7.549, 14.615, 15.377, 24.328, and 24.608, for example, characteristic peaks at 6.229, 7.549, 14.615, 15.377, 21.796, 24.328, 24.608, and 27.427, for example, characteristic peaks at 4.917, 6.229, 7.549, 14.615, 15.377, 16.487, 16.854, 21.796, 24.328, 24.608, 25.473, and 27.427.

[0288] 14. The maleate crystal form according to embodiment 13, characterized in that the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in Figure 10.

[0289] 15. A method for preparing a maleate crystal form as described in embodiment 13 or 14, the method comprising: adding a compound of formula 1 to ethanol, adding maleic acid, and stirring.

[0290] 16. A fumarate crystal form of the compound shown in Formula 1, characterized in that the X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 4.760, 14.588, and 19.450, for example, at 4.760, 11.938, 14.588, 19.450, and 21.705, for example, at 4.760, 9.204, 11.938, 14.588, 18.143, 19.450, 21.705, 25.258, and 28.413.

[0291] 17. The fumarate crystal form according to embodiment 16, characterized in that the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in Figure 20.

[0292] 18. A method for preparing a fumarate crystal form as described in embodiment 16 or 17, the method comprising: adding a compound of formula 1 to solvent II, adding fumaric acid, and stirring, wherein solvent II is selected from ethanol, acetone and tetrahydrofuran.

[0293] 19. A benzoate crystal form of the compound shown in Formula 1, characterized in that the X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 5.676, 11.524, 16.837, 17.189, and 23.016, for example, at 5.676, 11.524, 16.837, 17.189, 19.104, 20.647, 22.585, 23.016, and 27.186, for example, at 5.676, 8.921, 11.524, 13.931, 16.837, 17.189, 18.429, 19.104, 20.647, 22.585, 23.016, 27.186, and 27.909.

[0294] 20. The benzoate crystal form according to embodiment 19, characterized in that the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in Figure 23.

[0295] 21. A method for preparing a benzoate crystal form as described in embodiment 19 or 20, the method comprising: adding a compound of formula 1 to ethanol, adding a benzoic acid ethanol solution, and stirring.

[0296] 22. A cocrystal of the compound shown in Formula 1, wherein the ligands of the cocrystal are selected from saccharin, L-phenylalanine, L-tyrosine, L-tryptophan, L-histidine, L-aspartic acid, L-arginine, L-lysine and L-proline.

[0297] 23. The eutectic of the compound of formula 1 according to embodiment 22, characterized in that the chemical ratio of the compound of formula 1 to the ligand is 2:1 to 1:2, for example 1:1 or 1:2.

[0298] 24. A method for preparing a cocrystal of a compound of formula 1 as described in embodiment 22 or 23, comprising the step of reacting the compound of formula 1 with a ligand selected from saccharin, L-phenylalanine, L-tyrosine, L-tryptophan, L-histidine, L-aspartic acid, L-arginine, L-lysine and L-proline.

[0299] 25. A saccharin eutectic of the compound shown in Formula 1, characterized in that the X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 16.700, 17.339, 20.409, 20.747, and 24.370, for example, at 11.520, 16.700, 17.339, 20.409, 20.747, 23.313, 24.370, and 26.464, for example, at 11.520, 14.798, 15.492, 16.700, 17.339, 20.409, 20.747, 23.313, 24.370, 26.464, and 28.063.

[0300] 26. The saccharin eutectic of the compound of Formula 1 according to Embodiment 25, characterized in that the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in Figure 34.

[0301] 27. A method for preparing a saccharin cocrystal of a compound of formula 1 as described in embodiment 25 or 26, the method comprising: adding the compound of formula 1 to ethanol, adding saccharin, and stirring.

[0302] 28. According to any one of the implementation schemes 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, 25-26, the 2θ angle error range is ±0.20.

[0303] 29. A pharmaceutical composition comprising a pharmaceutically acceptable salt as described in embodiment 1 or 2, or a eutectic as described in embodiment 22 or 23, or a crystal form as described in any one of embodiments 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, 25-26, and optionally a pharmaceutically acceptable excipient.

[0304] 30. A method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable salt as described in embodiment 1 or 2, or a eutectic as described in embodiment 22 or 23, or a crystal form as described in any one of embodiments 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, 25-26, with a pharmaceutically acceptable excipient.

[0305] 31. Use of the pharmaceutically acceptable salt of embodiment 1 or 2, or the eutectic of embodiment 22 or 23, or the crystal form of any one of embodiments 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, 25-26, or the pharmaceutical composition of embodiment 29 in the preparation of a medicament for the prevention and / or treatment of cancer.

[0306] In some embodiments, the p-toluenesulfonate of the compound of formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 4-40°.

[0307] This disclosure also provides a method for preparing the amorphous p-toluenesulfonate of the compound shown in Formula 1, comprising adding the compound of Formula 1 to tetrahydrofuran, adding an ethanol solution of p-toluenesulfonate, and stirring.

[0308] In some embodiments, the methanesulfonate of the compound of formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 4-40°.

[0309] This disclosure also provides a method for preparing the amorphous methanesulfonate of the compound shown in Formula 1, comprising adding the compound of Formula 1 to ethyl acetate, adding a methanesulfonate ethanol solution, and stirring.

[0310] In some embodiments, the tartrate salt of the compound of formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 4-40°.

[0311] This disclosure also provides a method for preparing the amorphous tartrate salt of the compound shown in Formula 1, comprising adding the compound of Formula 1 to ethanol, adding a tartaric acid ethanol solution, and stirring.

[0312] In some embodiments, the citrate of the compound of formula 1 provided in this disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2θ range of 4-40°.

[0313] This disclosure also provides a method for preparing the amorphous citrate of the compound of Formula 1, comprising adding the compound of Formula 1 to tetrahydrofuran, adding a citric acid ethanol solution, and stirring.

[0314] This disclosure also provides a pharmaceutical composition comprising the following crystal forms of the aforementioned compound of Formula 1: hydrochloride crystal form I, hydrochloride crystal form III, hydrochloride crystal form III, sulfate crystal form I, sulfate crystal form III, sulfate crystal form III, phosphate crystal form I, phosphate crystal form II, phosphate crystal form III, tartrate crystal form I, maleate crystal form I, maleate crystal form II, maleate crystal form III, maleate crystal form IV, maleate crystal form V, maleate crystal form VI, p-toluenesulfonate crystal form I, p-toluenesulfonate crystal form II, and p-toluenesulfonate crystal form II. Crystal form III, p-toluenesulfonate crystal form IV, fumarate crystal form I, succinate crystal form I, succinate crystal form II, benzoate crystal form I, benzoate crystal form II, benzoate crystal form III, benzoate crystal form IV, hippurate crystal form I, hippurate crystal form II, mandelate crystal form I, acetate crystal form I, malate crystal form I, citrate crystal form I, hydrobromide crystal form I, saccharin cocrystal A, saccharin cocrystal B or saccharin cocrystal C, or pharmaceutically acceptable salts and cocrystals of compound 1, and pharmaceutical excipients optionally selected from pharmaceutically acceptable excipients.

[0315] This disclosure also provides a pharmaceutical composition comprising the following crystal forms of the aforementioned compound of Formula 1: hydrochloride crystal form I, hydrochloride crystal form III, hydrochloride crystal form III, sulfate crystal form I, sulfate crystal form III, sulfate crystal form III, phosphate crystal form I, phosphate crystal form II, phosphate crystal form III, tartrate crystal form I, maleate crystal form I, maleate crystal form II, maleate crystal form III, maleate crystal form IV, maleate crystal form V, maleate crystal form VI, p-toluenesulfonate crystal form I, p-toluenesulfonate crystal form II, and p-toluenesulfonic acid. The compound of Formula 1 is prepared from a pharmaceutically acceptable salt and cocrystal, and optionally from a pharmaceutically acceptable excipient.

[0316] This disclosure also provides a method for preparing a pharmaceutical composition, comprising mixing the aforementioned compound of Formula 1 in the following crystal forms: hydrochloride crystal form I, hydrochloride crystal form III, hydrochloride crystal form III, sulfate crystal form I, sulfate crystal form III, sulfate crystal form III, phosphate crystal form I, phosphate crystal form II, phosphate crystal form III, tartrate crystal form I, maleate crystal form I, maleate crystal form II, maleate crystal form III, maleate crystal form IV, maleate crystal form V, maleate crystal form VI, p-toluenesulfonate crystal form I, p-toluenesulfonate crystal form II, and p-toluenesulfonate crystal form III. The steps of mixing a pharmaceutically acceptable salt and cocrystal of a compound of formula 1 with a pharmaceutically acceptable excipient.

[0317] This disclosure also provides the following crystal forms of the aforementioned compound of Formula 1: hydrochloride crystal form I, hydrochloride crystal form III, hydrochloride crystal form I, sulfate crystal form III, sulfate crystal form III, phosphate crystal form I, phosphate crystal form II, phosphate crystal form III, tartrate crystal form I, maleate crystal form I, maleate crystal form II, maleate crystal form III, maleate crystal form IV, maleate crystal form V, maleate crystal form VI, p-toluenesulfonate crystal form I, p-toluenesulfonate crystal form II, p-toluenesulfonate crystal form III, p-toluenesulfonate crystal form IV, p-toluenesulfonate crystal form V, p-toluenesulfonate crystal form VI, p-toluenesulfonate crystal form I, p-toluenesulfonate crystal form II, p-toluenesulfonate crystal form III, p-toluenesulfonate crystal form III, p-toluenesulfonate crystal form IV, p-toluenesulfonate crystal form V, p-toluenesulfonate crystal form VI, p-toluenesulfonate crystal form III, p-toluenesulfonate crystal form VI ... The following are crystal forms: fumarate form IV, fumarate form I, succinate form I, succinate form II, benzoate form I, benzoate form II, benzoate form III, benzoate form IV, hippurate form I, hippurate form II, mandelate form I, acetate form I, malate form I, citrate form I, hydrobromide form I, saccharin cocrystal A, saccharin cocrystal B or saccharin cocrystal C, or pharmaceutical salts and cocrystals of the compound of formula 1, or the use of the foregoing composition in the preparation of a medicament for the prevention and / or treatment of cancer.

[0318] The uses described in this disclosure, wherein the cancers are selected from lung cancer (such as non-small cell lung cancer), kidney cancer, liver cancer (such as hepatocellular carcinoma), head and neck cancer, esophageal cancer (also called esophageal cancer), lymphoma (such as diffuse large B-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, T-cell or B-cell-derived lymphoid malignancies, follicular lymphoma), glioblastoma, glioblastoma, colorectal cancer (such as colon cancer and rectal cancer), malignant peripheral nerve sheath tumor (MP). NST, also known as malignant peripheral nerve sheath tumor, melanoma, gastric cancer, pancreatic cancer, bile duct cancer, bladder cancer, breast cancer, ovarian cancer, vaginal cancer, cervical cancer, endometrial cancer, prostate cancer, testicular cancer, seminoma, myeloma (such as multiple myeloma), leukemia (such as acute leukemia, chronic leukemia, myeloid leukemia, myelofibrosis, erythroleukemia), acoustic neuroma, basal cell carcinoma, brain cancer, bronchial cancer, sarcoma (such as chondrosarcoma, soft tissue sarcoma, fibrosarcoma, smooth muscle cell carcinoma). Sarcoma, liposarcoma, lymphangiosarcoma, myxosarcoma, osteoblastic sarcoma, rhabdomyosarcoma, Ewing's sarcoma), choriocarcinoma, craniopharyngioma, cystadenocarcinoma, hemangioendothelioma, ependymoma, epithelial carcinoma, glioma, astrocytoma, hemangioblastoma, medulloblastoma, meningioma, mesothelioma, neuroblastoma, bone cancer, nasopharyngeal carcinoma, oral cancer, laryngeal cancer, thyroid cancer, retinoblastoma, skin cancer, squamous cell carcinoma (such as head and neck squamous cell carcinoma), synovoma, sweat gland carcinoma, and myelocystitis. Abnormal syndrome; in some embodiments, the cancer is selected from ovarian cancer, lymphoma, pancreatic cancer, bladder cancer, gastric cancer, colorectal cancer, bile duct cancer, mesothelioma, malignant peripheral nerve sheath tumor (MPNST), glioblastoma and lung cancer; in some embodiments, the cancer is selected from lung cancer, mesothelioma, malignant peripheral nerve sheath tumor (MPNST) and pancreatic cancer; in some embodiments, the cancer is selected from liver cancer, breast cancer, skin cancer, bladder cancer, pancreatic cancer and head and neck cancer.

[0319] In some implementations, the cancers described in this disclosure are MTAP-related cancers.

[0320] In some implementations, the lung cancer described in this disclosure is non-small cell lung cancer.

[0321] The "2θ or 2θ angle" mentioned in this disclosure refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree; the error range of 2θ for each characteristic peak is ±0.20 (including the case where the number has more than one decimal place after rounding), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0322] The numerical values ​​in this disclosure, such as those relating to the content of certain substances, are calculated data and inevitably contain a certain degree of error. Generally, ±10% is within the reasonable error range. The error may vary to some extent depending on the context in which it is used, but this variation shall not exceed ±10%, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0323] The starting material used in the crystal form preparation method disclosed herein can be any form of compound, including but not limited to: amorphous, arbitrary crystal form, hydrate, solvate, etc. The drying temperature described in this disclosure is generally 25℃-100℃, preferably 40℃-70℃, and can be dried under normal pressure or reduced pressure.

[0324] The crystallization methods described in this disclosure include stirred crystallization, static crystallization, room temperature crystallization, cooled crystallization, solvent evaporation crystallization, and seed crystallization induction. The cooling temperature is selected from below 65°C, preferably from -10°C to 60°C. Stirring may also be performed during the crystallization process. In some embodiments, the crystallization is stirred crystallization. In some embodiments, the crystallization is static crystallization.

[0325] The term "eutectic" refers to a crystalline material composed of two or more different molecules associated in the same lattice by nonionic and noncovalent bonds, one of which is an API.

[0326] The “differential scanning calorimetry or DSC” described in this disclosure refers to measuring the temperature difference and heat flow difference between the sample and the reference material during the sample heating or isothermal process, in order to characterize all physical and chemical changes related to thermal effects and obtain phase transition information of the sample.

[0327] According to the description of hygroscopic characteristics and the definition of hygroscopic weight gain in the "Guiding Principles on Hygroscopicity of Drugs" in Part IV of the 2020 edition of the Chinese Pharmacopoeia,

[0328] Deliquescence: Absorbs sufficient moisture to form a liquid;

[0329] Extremely hygroscopic: the weight gain due to hygroscopic absorption is not less than 15%;

[0330] It has hygroscopic properties: the weight gain due to hygroscopic absorption is less than 15% but not less than 2%;

[0331] Slightly hygroscopic: the weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0332] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0333] The “excipients” described in this disclosure include, but are not limited to, any adjuvants, carriers, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or livestock. Attached Figure Description

[0334] Figure 1 shows the amorphous XRPD spectrum of compound 1.

[0335] Figure 2 shows the XRPD spectrum of the hydrochloride crystal form I of compound formula 1.

[0336] Figure 3 shows the XRPD spectrum of sulfate crystal form I of compound formula 1.

[0337] Figure 4 shows the XRPD spectrum of the sulfate crystal form ⅠI of compound 1.

[0338] Figure 5 shows the XRPD spectrum of sulfate crystal form III of compound 1.

[0339] Figure 6 shows the XRPD spectrum of phosphate crystal form I of compound 1.

[0340] Figure 7 shows the XRPD spectrum of phosphate crystal form II of compound 1.

[0341] Figure 8 shows the XRPD spectrum of phosphate crystal form III of compound 1.

[0342] Figure 9 shows the XRPD spectrum of tartrate crystal form I of compound 1.

[0343] Figure 10 shows the XRPD spectrum of maleate crystal form I of compound 1.

[0344] Figure 11 shows the XRPD spectrum of maleate crystal form II of compound 1.

[0345] Figure 12 shows the XRPD spectrum of maleate crystal form III of compound 1.

[0346] Figure 13 shows the XRPD spectrum of maleate crystal form IV of compound 1.

[0347] Figure 14 shows the XRPD spectrum of maleate crystal form V of compound 1.

[0348] Figure 15 shows the XRPD spectrum of maleate crystal form VI of compound 1.

[0349] Figure 16 shows the XRPD spectrum of p-toluenesulfonate crystal form I of compound 1.

[0350] Figure 17 shows the XRPD spectrum of compound p-toluenesulfonate II of Formula 1.

[0351] Figure 18 shows the XRPD spectrum of compound p-toluenesulfonate III of Formula 1.

[0352] Figure 19 shows the XRPD spectrum of p-toluenesulfonate crystal form IV of compound 1.

[0353] Figure 20 shows the XRPD spectrum of fumarate crystal form I of compound formula 1.

[0354] Figure 21 shows the XRPD spectrum of succinate crystal form I of compound 1.

[0355] Figure 22 shows the XRPD spectrum of succinate form II of compound 1.

[0356] Figure 23 shows the XRPD spectrum of benzoate I of Formula 1.

[0357] Figure 24 shows the XRPD spectrum of benzoate form II of compound 1.

[0358] Figure 25 shows the XRPD spectrum of benzoate form III of compound 1.

[0359] Figure 26 shows the XRPD spectrum of benzoate form IV of compound 1.

[0360] Figure 27 shows the XRPD spectrum of hippurate crystal form I of compound 1.

[0361] Figure 28 shows the XRPD spectrum of compound II hippurate of Formula 1.

[0362] Figure 29 shows the XRPD spectrum of mandelate crystal form I of compound 1.

[0363] Figure 30 shows the XRPD spectrum of the acetate crystal form I of compound 1.

[0364] Figure 31 shows the XRPD spectrum of compound I, malate salt.

[0365] Figure 32 shows the XRPD spectrum of citrate crystal form I of compound 1.

[0366] Figure 33 shows the XRPD spectrum of hydrobromide crystal form I of compound 1.

[0367] Figure 34 shows the XRPD spectrum of saccharin eutectic A, a compound of Formula 1.

[0368] Figure 35 shows the XRPD spectrum of saccharin eutectic B, a compound of Formula 1.

[0369] Figure 36 shows the XRPD spectrum of saccharin eutectic C, a compound of Formula 1.

[0370] Figure 37 shows the XRPD spectrum of the hydrochloride crystal form ⅠI of compound 1.

[0371] Figure 38 shows the XRPD spectrum of the hydrochloride crystal form III of compound 1.

[0372] Figure 39 shows the efficacy data of compound of formula 1 on Lu99 xenografts in NUNU nude mice.

[0373] Figure 40 shows the effect of compound 1 on the body weight of NUNU nude mice. Detailed Implementation

[0374] The present disclosure will be explained in more detail below with reference to embodiments or experimental examples. The embodiments or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure and are not intended to limit the substance and scope of the present disclosure.

[0375] Test conditions of the instruments used in the experiment:

[0376] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0377] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a waters ACQuity UPLC-QD / SQD system (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), or a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0378] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0379] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0380] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0381] XRPD (X-ray Powder Diffraction) was used for analysis: measurements were performed using a BRUKER D8 X-ray diffractometer. Specific data collected included: Cu anode (40 kV, 40 mA), Cu-Kα1 rays. Kα2 rays Kβ rays Scanning mode: θ / 2θ, scanning range (2θ range): 3°~40°.

[0382] DSC stands for Differential Scanning Calorimetry: Measurements were performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10℃ / min. The specific temperature range was referenced from the corresponding spectra (mostly 25-350℃), and the nitrogen purging rate was 50mL / min.

[0383] TGA is thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA2 thermogravimetric analyzer, with a heating rate of 10℃ / min, and the specific temperature range was referenced from the corresponding spectrum (mostly 30-350℃). The nitrogen purging rate was 50mL / min.

[0384] DVS stands for Dynamic Moisture Adsorption: The detection method is SMSDVS Advantage. At 25℃, the humidity changes from 50% to 95% to 0% to 95% to 50%, with a step size of 10% (the last step is 5%). (The specific humidity range is subject to the corresponding spectrum. The methods listed here are the most commonly used methods.) The judgment criteria are dm / dt not greater than 0.002% / min and Tmax not greater than 360min.

[0385] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0386] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0387] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0388] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0389] Example 1: Preparation of Compound 1

[0390] (M)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutan[e][1,4]dioxane-4-carboxylonitrile 1 (Refer to the preparation method of compound 2-p1 in patent application PCT / CN2024 / 110882)

[0391] first step

[0392] 2-(2-bromo-4,6-difluorophenoxy)cyclobut-1-one 1c

[0393] 2-Bromo-4,6-difluorophenol 1b (473 g, 2.04 mol, Jiangsu Aikon) was dissolved in N,N-dimethylformamide (3000 mL), and sodium carbonate (997.14 g, 9.41 mol) and 2-bromocyclobutanone 1a (410.08 g, 2.34 mol, prepared by the method disclosed in Intermediate I-07A on page 53 of patent application "WO2018013770") were added. The mixture was stirred at 80 °C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with 4000 mL of ethyl acetate. The filtrate was collected, and 4000 mL of water was added to separate the organic phase. The aqueous phase was extracted once with 500 mL of ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 1c (260 g, yield: 46%).

[0394] MS m / z(ESI):276.9[M+1].

[0395] Step 2

[0396] 2-(2-bromo-4,6-difluorophenoxy)cyclobut-1-ol 1d

[0397] Compound 1c (240 g, 822.92 mmol) was dissolved in tetrahydrofuran (1500 mL), cooled to -70 °C, and a 1 M solution of tri-sec-butylborohydride in tetrahydrofuran (905 mL) was added dropwise. The mixture was stirred for 1 hour while maintaining the temperature. The solution was then quenched with 500 mL of water, followed by the addition of 500 mL of 1% sodium hydroxide solution. The mixture was extracted with ethyl acetate (500 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure to obtain the crude title compound 1d (272 g). The product was used directly in the next reaction without purification. MS m / z (ESI): 278.9 [M+1].

[0398] Step 3

[0399] 4-Bromo-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutan[e][1,4]dioxanecyclo1e

[0400] Compound 1d (272 g, 779.71 mmol) was dissolved in dimethyl sulfoxide (2700 mL), and cesium carbonate (762.13 g, 2.34 mol) was added. The mixture was heated to 120 °C and stirred for 1 hour. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (500 mL × 2). The organic phases were combined, washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 1e (201 g, yield: 69.7%).

[0401] MS m / z(ESI):258.9[M+1].

[0402] Step 4

[0403] 6-Fluoro-1,2,2a,8a-Tetrahydrobenzo[b]cyclobutan[e][1,4]dioxane-4-carboxynitrile 1f

[0404] Compound 1e (5.45 g, 21 mmol) was dissolved in N,N-dimethylacetamide (50 mL), and zinc cyanide (4.94 g, 42 mmol), zinc powder (1.44 g, 22.1 mmol), and tetrakis(triphenylphosphine)palladium (1.2 g, 1.05 mmol) were added. The mixture was purged with nitrogen and heated to 100 °C for 16 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and filtered. The filtrate was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 1f (3.52 g, yield: 81.5%).

[0405] MS m / z(ESI):206.2[M+1].

[0406] Step 5

[0407] 6-Fluoro-5-iodo-1,2,2a,8a-tetrahydrobenzo[b]cyclobutan[e][1,4]dioxane-4-carboxynitrile 1g

[0408] Compound 1f (2.32 g, 11.3 mmol) was dissolved in tetrahydrofuran (80 mL), cooled to -78 °C, and 6.3 mL of a 2 M diisopropylaminolithium tetrahydrofuran solution was added dropwise. After stirring for 30 minutes, 10 mL of a tetrahydrofuran solution of iodine (3.0 g, 11.8 mmol) was added, and the reaction was stirred for 30 minutes. The reaction was quenched by adding saturated sodium sulfite solution and sodium bicarbonate aqueous solution. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give compound 1 g (1.5 g, yield: 40%).

[0409] Step 6

[0410] 6-Fluoro-5-(1-(methyl-d3)-1H-pyrazol-5-yl)-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxynitrile 1i

[0411] 1-(methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1H-pyrazole 1h (3g, 14.2mmol, according to the Example on page 178 of the specification in patent application "WO2019079469"). 25) prepared by the disclosed method) and 1 g (2.4 g, 7.25 mmol) of compound were dissolved in water (8 mL) and 1,4-dioxane (40 mL), and sodium carbonate (1.6 g, 15.1 mmol) and 1,1'-bis(di-tert-butylphosphine)ferrocene dipalladium chloride (470 mg, 718.9 μmol) were added. The mixture was purged with nitrogen and heated to 85 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1i (2 g, yield: 99%).

[0412] MS m / z(ESI):289.0[M+1].

[0413] Step 7

[0414] 5-(4-bromo-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxynitrile 1j

[0415] Compound 1i (1.9 g, 6.6 mmol) was dissolved in acetonitrile (40 mL), and N-bromosuccinimide (1.3 g, 7.25 mmol) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 1j (2.1 g, yield: 86.7%).

[0416] MS m / z(ESI): 367.2 [M+1].

[0417] Step 8

[0418] 5-(4-(4-((1,3-dioxoisoindoline-2-yl)methyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxanecyclo-4-carboxynitrile 1l

[0419] Under a nitrogen atmosphere, compound 1j (1.5 g, 4.08 mmol), compound 1k (1.8 g, 4.17 mmol, prepared by the method disclosed in the literature "Journal of Medicinal Chemistry, 2022, vol. 65, #3, p. 1749-1766"), 1,1'-bis(di-tert-butylphosphine)ferrocene dipalladium chloride (2.7 g, 4 mmol) and sodium bicarbonate (686 mg, 8.17 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL). The mixture was stirred at 80 °C for 4 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give title compound 1l (760 mg, yield: 31.4%).

[0420] MS m / z(ESI): 592.2 [M+1].

[0421] Steps 9 and 10

[0422] 5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxynitrile 1m

[0423] (M)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxylonitrile

[0424] (M)-(2aR,8aS)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxylon 2

[0425] (P)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxylonitrile3

[0426] (P)-(2aR,8aS)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutane[e][1,4]dioxane-4-carboxylonitrile

[0427] Compound 1L (760 mg, 1.28 mmol) was dissolved in ethanol (15 mL), and hydrazine hydrate (605 mg, 10.2 mmol, 85% purity) was added. The mixture was stirred at 80 °C for 2 hours. The reaction solution was concentrated under reduced pressure. Dichloromethane / methanol (V:V = 5:1) was added to the residue, and the mixture was stirred for 10 minutes and then filtered. The filtrate was concentrated under reduced pressure to obtain crude compound 1M (590 mg). The crude compound 1M was purified by preparative high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs, Prep 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-42%, flow rate: 30 mL / min) to obtain two fractions: fraction A (short retention time, 130 mg, yield: 22%) and fraction B (long retention time, 130 mg, yield: 22%).

[0428] Component A (130 mg) was resolved by a chiral column (Gilson-281, column: CHIRALPAK IE, 20*250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% 7M ammonia methanol solution), gradient ratio: A:B = 50:50, flow rate: 15 mL / min) to give compound 4 (30 mg, 23%) and compound 1 (30 mg, 23%).

[0429] The single configuration 4 compound (shorter retention time in component A) (30 mg, 23%).

[0430] Chiral HPLC analysis: retention time 13.617 min, purity: 99% (column: CHIRALPAK IG 150*4.6mm, 5μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 50:50, flow rate: 1.0 mL / min).

[0431] MS m / z(ESI):462.1[M+1].

[0432] 1 H NMR (500MHz, CD3OD): δ8.30(d,1H),8.15(s,1H),7.77(d,1H),7.70(dd,1H),7.33(d,1H),4.11-4.00(m,2H),3.34-3.32(m,2H),2.37-2.17(m,4H).

[0433] Compound with single configuration 1 (longer retention time in component A): (30 mg, 23%).

[0434] X-ray powder diffraction analysis showed that the compound of formula 1 was amorphous, and the XRPD spectrum is shown in Figure 1.

[0435] Chiral HPLC analysis: retention time 18.128 min, purity: 98% (column: CHIRALPAK IE 150*4.6mm, 5μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 50:50, flow rate: 1.0 mL / min).

[0436] MS m / z(ESI):462.1[M+1].

[0437] 1 H NMR (500MHz, DMSO-d6): δ12.44(s,1H),8.25(s,1H),8.19-8.17(m,1H),7.76-7.74(m,1H),7.71-7.7 0(m,1H),7.60-7.58(m,1H),4.97-4.90(m,2H),3.80-3.73(m,2H),2.26-2.13(m,4H),1.91(brs,2H).

[0438] Component B (130 mg) was resolved by a chiral column (Gilson-281, column: CHIRALPAK IE, 20*250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% 7M ammonia methanol solution), gradient ratio: A:B = 50:50, flow rate: 15 mL / min) to give compound 3 (30 mg, 23%) and compound 2 (47 mg, 36.1%).

[0439] Compound with single configuration 3 (shorter retention time in component B): (30 mg, 23%).

[0440] Chiral HPLC analysis: retention time 13.073 min, purity: 99% (column: CHIRALPAK IE 150*4.6mm, 5μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 50:50, flow rate: 1.0 mL / min).

[0441] MS m / z(ESI):462.1[M+1].

[0442] 1 H NMR (500MHz, DMSO-d6): δ12.42(s,1H),8.24(s,1H),8.15-8.14(m,1H),7.74-7.73(m,1H),7.68-7.6 6(m,1H),7.59-7.57(m,1H),4.96-4.89(m,2H),3.81-3.74(m,2H),2.26-2.11(m,4H),1.82(brs,2H).

[0443] Compound with single configuration 2 (longer retention time in component B): (47 mg, 36.1%).

[0444] Chiral HPLC analysis: retention time 23.504 min, purity: 99% (column: CHIRALPAK IE 150*4.6mm, 5μm; mobile phase: n-hexane and ethanol (containing 0.1% diethylamine), gradient ratio: A:B 50:50, flow rate: 1.0 mL / min).

[0445] MS m / z(ESI):462.1[M+1].

[0446] 1¹H NMR (500 MHz, CD₃OD): δ 8.27 (d, 1H), 8.15 (s, 1H), 7.73 (d, 1H), 7.68 (dd, 1H), 7.33 (d, 1H), 4.07 - 3.97 (m, 2H), 3.38 - 3.34 (m, 2H), 2.35 - 2.21 (m, 4H).

[0447] Test Example 1 HCT116 and HCT116 MTAP⁻ / ⁻ Cell Proliferation Experiment

[0448] I. Experimental Materials and Instruments

[0449] 1. HCT116 cell line (Nanjing Kebai, CBP60028)

[0450] 2. HCT116 MTAP⁻ / ⁻ cell line (Nanjing Kebai, CBP75002)

[0451] 3. DMSO (Sigma, D2650)

[0452] 4. McCoy's 5A medium (Gibco, 16600 - 082)

[0453] 5. Fetal bovine serum (FBS) (Gibco, 10091148)

[0454] 6. Phosphate - buffered saline (DPBS) pH 7.4 (Gibco, 14190 - 144)

[0455] 7. Pen strep (PS) (Gibco, 15140 - 122)

[0456] 8. 0.25% Trypsin - EDTA (1×) (Gibco, 25200 - 072)

[0457] 9. Luminescent Cell Viability Assay (Promega, G7572)

[0458] 10. 96 - well round bottom plate (JET / Jiet, TCP002096)

[0459] 11. 96 - well black clear bottom cell culture plate (Xinyou Biotechnology, 060096)

[0460] 12. 1.2 mL 96 - well deep well plate, transparent, sterile, square holes, V - bottom (Titan / Taitan, 02089063)

[0461] 13. 15 mL centrifuge tube (Titan / Taitan)

[0462] 14. Biosafety Cabinet (Thermo, 1300AII)

[0463] 15. Cell counter (Countstar, IC1000)

[0464] 16. Incubator (Thermo, I160)

[0465] 17. Centrifuge (Beckman Coulter, Allegra X-12 centrifuge)

[0466] 18. PHERAstar FS Microplate Reader (BMG Labtech)

[0467] II. Experimental Procedure

[0468] 1. Cell plating (Day 0)

[0469] a) Observe the cell state under a microscope to ensure that the cell confluence is ~90%.

[0470] b) Discard the cell supernatant, rinse once with PBS, and discard the PBS. Add an appropriate amount of trypsin to digest the cells, and incubate at 37°C for 3 minutes.

[0471] c) Terminize digestion with an equal volume of McCoy's 5A medium containing 10% FBS, and collect the cell suspension. Centrifuge at 300g for 3 minutes. Resuspend the cells in an appropriate amount of fresh culture medium.

[0472] d) Take the resuspended cell suspension and count the cells.

[0473] e) Dilute the cell suspension to 1e4 / mL with McCoy's 5A medium containing 10% FBS, 50 μL / well. For HCT116, use 500 cells / well; for HCT116 MTAP- / -, use 500 cells / well.

[0474] f) Incubate the cell plates overnight in an incubator at 37°C with 5% carbon dioxide.

[0475] 2. Administer medication (Day 1)

[0476] a) Dilute each compound to 9 concentration points using DMSO (starting concentration 10000 μM, 3-fold dilution; different compounds according to IC50). 50 (Different maximum concentrations can be adjusted accordingly). For example, in a 96-well round-bottom plate, 5 μL of the compound is serially diluted to 10 μL of DMSO.

[0477] b) Dilute each compound at each concentration point by 250 times into the corresponding volume of McCoy's 5A medium.

[0478] c) Add 50 μL of the diluted compound solution to each well of cell supernatant in each cell plate.

[0479] d) Place the cell plate after drug administration in an incubator at 37°C with 5% carbon dioxide for incubation.

[0480] 3. Re-digest the plaster and add medication (Day 5)

[0481] a) Five days after drug administration, discard the drug-containing culture medium, then add 100 μL / well of PBS to rinse once, and immediately remove the PBS.

[0482] b) Add 25 μL of trypsin to digest the cells, incubate at 37°C for 3 minutes, and then add McCoy's 5A medium containing 10% FBS at 175 μL / well to terminate the digestion.

[0483] c) Mix the cells by pipetting with a pipette and re-plate them at a ratio of 1:20, i.e., aspirate 10 μL of cell suspension into a new 96-well plate (pre-fill the new plate with 40 μL of McCoy's 5A medium containing 10% FBS).

[0484] d) Prepare and add the compound according to steps a) to c) in section 2, 50 μL per well.

[0485] e) Place the cell plate after drug administration in an incubator at 37°C with 5% carbon dioxide for incubation.

[0486] 4. CTG test (day 10)

[0487] a) Before use, allow the CellTiter-Glo buffer and lyophilized CellTiter-Glo substrate to equilibrate to room temperature, mix them thoroughly to prepare 100 mL of CellTiter-Glo reagent (or take the mixed CellTiter-Glo reagent out of -20℃ and equilibrate to room temperature).

[0488] b) Remove the plate to be tested from the incubator, equilibrate to room temperature, and add 50 μL of CellTiter-Glo reagent to each well.

[0489] c) Shake and mix for 2 minutes to allow the cells to fully lyse.

[0490] d) After the signal stabilizes at room temperature for 28 minutes, it is detected on a Pherastar FS.

[0491] Comparative Example 1 (refer to WO2022192745A1, Example 16 - 90), the structure is as follows

[0492] Table 1 IC of the compounds of the present disclosure against the growth inhibition of HCT116 MTAP- / - cells 50 value

[0493] Conclusion: The compound of formula 1 has a good selective inhibitory effect on the growth of HCT116 MTAP- / - cells. Compared with Comparative Example 1, the compound of formula 1 has a better inhibitory effect on the growth of HCT116 MTAP- / - cells.

[0494] Test Example 2 Pharmacodynamic experiment

[0495] 1. Experimental purpose

[0496] To evaluate the growth inhibitory effect of the compound of formula 1 on subcutaneous xenograft tumors of human giant cell lung cancer cell line Lu99 in female NUNU nude mice.

[0497] 2. Experimental drugs

[0498] The compound of formula 1.

[0499] Use a solution of 20% PEG400 + 70% (10% TPGS) + 5% DMSO + 5% (1% HPMCK100LV).

[0500] 3. Experimental methods and experimental materials

[0501] 3.1 Experimental animals and feeding conditions

[0502] Experimental animals: NUNU nude mice, female, purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd. (license number: SCXK(Zhe)2024 - 0001, animal certificate number: 20240524Abzz0619000789), with a body weight of about 20 - 24 g when purchased. [[ID=​​​​​​​​​​​​​​​3.3 Experimental Methods:

[0508] 0.1 ml (5 × 10⁻⁶) of water in the logarithmic growth phase was used. 5 Lu99 cells (1:1 volume ratio with 50% Matrigel) were subcutaneously inoculated into the right upper limb of each mouse, resulting in an average tumor volume of 75 mm². 3 The mice were randomly divided into four groups of 12 mice each, based on tumor volume and body weight, as shown in Table 4. The day of grouping was designated D0, and administration began once or twice daily via gavage for 21 days. Day 21 after administration was designated D21 (Table 1-2). Tumor volume was measured twice weekly using calipers, and body weight was measured twice weekly, with data recorded.

[0509] 3.4 Data Statistics

[0510] All data were plotted and statistically analyzed using Excel and GraphPad Prism 10 software.

[0511] The formula for calculating tumor volume (V) is: V = 1 / 2 × a × b 2 Where a and b represent length and width, respectively.

[0512] Relative tumor proliferation rate T / C (%) = (T - T0) / (C - C0) × 100 (%), where T and C are the tumor volumes of the treatment group and control group at the end of the experiment; T0 and C0 are the tumor volumes at the beginning of the experiment. Tumor inhibition rate TGI (%) = 100 - T / C (%).

[0513] 4. Results

[0514] The efficacy data of compound 1 against Lu99 xenografts in NUNU nude mice are shown in Tables 1-2 and Figure 39.

[0515] The effect of compound 1 on the body weight of NUNU nude mice is shown in Figure 40.

[0516] Table 1-2. Efficacy of Compound 1 against Lu99 xenografts in NUNU nude mice. Note: qd means once a day; d means day; ig means gavage; SEM means standard error.

[0517] 5. Conclusion

[0518] Compound of Formula 1, administered once daily for 21 days, showed a tumor inhibition rate of 72% in the low-dose group (50 mpk / qd), 90% in the medium-dose group (100 mpk / qd), and 95% in the high-dose group (200 mpk / qd). The administration had no effect on the body weight of the mice.

[0519] Test Example 3: Pharmacokinetic Evaluation

[0520] I. Nu / Nu Mouse Experiment

[0521] 1. Abstract

[0522] Nu / Nu mice were used as test animals. The plasma concentration of compound 1 was determined at different time points after gavage (ig) administration to Nu / Nu mice using LC / MS / MS. The pharmacokinetic behavior of compound 1 in Nu / Nu mice was studied and its pharmacokinetic characteristics were evaluated.

[0523] 2. Test Plan

[0524] 2.1 Test Drugs

[0525] Compound of Formula 1 and Comparative Example 1.

[0526] 2.2 Experimental Animals

[0527] Eighteen female Nu / Nu mice were provided by Vital River Laboratory Animal Technology Co., Ltd., and divided into two groups on average.

[0528] 2.3 Drug Preparation

[0529] Weigh out a certain amount of the test compound and add 5% DMSO + 20% PEG400 + 70% (10% TPGS) + 5% (1% HMPC K100LV) to prepare a 10 mg / mL colorless and clear solution.

[0530] 2.4. Administration

[0531] The dosage is 100 mg / kg, and the administration volume is 10 mL / kg.

[0532] 3. Operation

[0533] Mice were not fasted. After gavage administration, and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, 0.1 mL of blood was collected from the orbital cavity and placed in EDTA-K2 anticoagulant tubes. Plasma was separated by centrifugation at 10,000 rpm for 1 minute (4°C) and stored at -20°C for analysis within 1 hour. The entire process, from blood collection to centrifugation, was performed under ice bath conditions.

[0534] To determine the content of the target compounds in the plasma of Nu / Nu mice after administration of different compounds: 20 μL of plasma samples from Nu / Nu mice at various time points after administration were taken, and 200 μL of acetonitrile and 25 μL of verapamil (100 ng / mL) were added. The mixture was vortexed for 5 minutes and centrifuged at 4000 rpm for 15 minutes. 90 μL of water and 90 μL of supernatant were vortexed for 5 minutes, and 2 μL of the supernatant (compound of Formula 1) and 0.5 μL of the supernatant (Comparative Example 1) were injected for LC / MS / MS analysis.

[0535] 4. Pharmacokinetic Parameter Results

[0536] Table 1-3 Pharmacokinetic parameters of the compounds disclosed herein in Nu / Nu mice

[0537] Conclusion: Compared with Comparative Example 1, Compound Formula 1 exhibits higher blood drug concentrations, higher exposure, and lower clearance in Nu / Nu mice, demonstrating pharmacokinetic advantages.

[0538] Example 2: Preparation of Crystal Form I of Compound Hydrochloride of Formula 1

[0539] 100 mg of compound 1 was added to 1 mL of ethyl acetate, followed by 113.8 μL of 2 M hydrochloric acid-ethanol solution. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product.

[0540] X-ray powder diffraction analysis identified the product as hydrochloride crystal form I. The XRPD spectrum is shown in Figure 2, and the characteristic peak positions are listed in Table 2. Ion chromatography analysis revealed a chloride ion content of 6.99%. The DSC spectrum showed an endothermic peak at 321.50℃. The TGA spectrum showed no significant weight loss.

[0541] DVS testing showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample's moisture absorption weight gain was approximately 0.47%; under accelerated testing conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 0.57%; and under extreme conditions (90% RH), the moisture absorption weight gain was approximately 0.94%. Furthermore, retesting of the crystal form after DVS testing showed no change in crystal form.

[0542] Table 2

[0543] Example 2-1: Preparation of Crystal Form I of Compound Hydrochloride of Formula 1

[0544] 100 mg of compound 1 was added to 1 mL of the solvent in Table 2-1, followed by 113.8 μl of 2M hydrochloric acid-ethanol solution. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was hydrochloride crystal form I.

[0545] Table 2-1

[0546] Example 3: Preparation of sulfate crystal form I of compound 1

[0547] Add 6 mg of compound 1 to 0.2 mL of acetone, then add 6.83 μL of 2 M sulfuric acid aqueous solution, stir to induce crystallization, centrifuge, collect the solid and dry under vacuum to obtain the product.

[0548] X-ray powder diffraction analysis identified the product as sulfate crystal form I. The XRPD spectrum is shown in Figure 3, and the characteristic peak positions are listed in Table 3. Ion chromatography determined the sulfate content to be 18.33%. The DSC spectrum showed endothermic peaks at 77.48 °C and 301.27 °C. The TGA spectrum showed a weight loss of 4.99% from 31 °C to 120 °C.

[0549] Table 3

[0550] Example 3-1: Preparation of sulfate crystal form I of compound 1

[0551] Add 6 mg of compound 1 to 0.2 mL of the solvent in Table 3-1, then add 6.83 μL of 2M sulfuric acid aqueous solution, stir to induce crystallization, centrifuge, collect the solid and dry under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product is sulfate crystal form I.

[0552] Table 3-1

[0553] Example 4: Preparation of sulfate crystal form IⅠ of compound 1

[0554] 100 mg of compound of formula 1 was added to 2 mL of ethyl acetate, followed by 227.6 μL of 2M sulfuric acid aqueous solution. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product.

[0555] X-ray powder diffraction analysis identified the product as sulfate crystal form IⅠ. The XRPD spectrum is shown in Figure 4, and the characteristic peak positions are listed in Table 4. Ion chromatography analysis revealed a sulfate content of 31.95%. DSC spectroscopy showed endothermic peaks at 82.82, 164.30, and 272.18 °C. TGA spectroscopy showed a weight loss of 1.76% from 31 °C to 120 °C.

[0556] DVS testing showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample's moisture absorption weight gain was approximately 2.30%; under accelerated testing conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 2.80%; and under extreme conditions (90% RH), the moisture absorption weight gain was approximately 68.60%. Furthermore, retesting of the crystal form after DVS testing showed no change in crystal form.

[0557] Table 4

[0558] Example 5: Preparation of the sulfate crystal form IⅠI of compound 1

[0559] 100 mg of the compound shown in Formula 1 was added to 2 mL of ethanol, followed by 113.8 μL of 2M sulfuric acid aqueous solution. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product.

[0560] X-ray powder diffraction analysis identified the product as sulfate crystal form IIII. The XRPD spectrum is shown in Figure 5, and the characteristic peak positions are listed in Table 5. Ion chromatography determined the sulfate content to be 17.20%. The DSC spectrum showed an endothermic peak at 260.09℃. The TGA spectrum showed a weight loss of 0.24% from 30℃ to 140℃.

[0561] Table 5

[0562] Example 6: Preparation of phosphate crystal form I of compound of formula 1

[0563] Add 6 mg of compound 1 to 0.2 mL of ethyl acetate, add 6.83 μL of 2 M phosphate ethanol solution, stir to induce crystallization, centrifuge, collect the solid and dry under vacuum to obtain the product.

[0564] X-ray powder diffraction analysis identified the product as phosphate crystal form I. The XRPD spectrum is shown in Figure 6, and the characteristic peak positions are listed in Table 6. Ion chromatography determined the phosphate content to be 31.41%. DSC spectroscopy showed endothermic peaks at 45.49, 168.15, and 289.13 °C. TGA spectroscopy showed a weight loss of 0.89% from 32 °C to 100 °C.

[0565] Table 6

[0566] Example 7: Preparation of phosphate crystal form II of compound of formula 1

[0567] Add 6 mg of compound 1 to 0.2 mL of ethanol, then add 6.83 μL of 2 M phosphate ethanol solution, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0568] X-ray powder diffraction analysis identified the product as phosphate crystal form II. The XRPD spectrum is shown in Figure 7, and the characteristic peak positions are listed in Table 7. Ion chromatography analysis revealed a phosphate content of 19.36%. DSC spectroscopy showed endothermic peaks at 126.52, 196.35, and 208.85 °C. TGA spectroscopy showed a weight loss of 0.34% between 31 °C and 120 °C, and a weight loss of 4.54% between 120 °C and 270 °C.

[0569] Table 7

[0570] Example 8: Preparation of phosphate crystal form III of compound of formula 1

[0571] Compound of Formula 1 (740 mg, 1.60 mmol) was added to ethanol (30 mL) to form a white suspension. Phosphoric acid (162.72 mg, 1.66 μmol, dissolved in 4 mL ethanol and added dropwise to the reaction solution) was then added, forming a white suspension. The mixture was stirred for 24 h, filtered, and the filter cake was collected and dried under vacuum to obtain the product (800 mg, yield: 89%). Ion chromatography showed that the phosphate ion content was 9.98%.

[0572] X-ray powder diffraction analysis determined that the crystal form was phosphate crystal form III. The X-ray powder diffraction pattern is shown in Figure 8, and the positions of its characteristic peaks are shown in Table 8.

[0573] The DSC spectrum shows endothermic peaks at 69.32℃, 194.65℃, and 231.95℃. The TGA spectrum shows a weight loss of 1.11% between 30℃ and 75℃.

[0574] Table 8

[0575] Example 9: Preparation of Tartrate Crystal Form I of Compound Formula 1

[0576] Add 6 mg of compound 1 to 0.2 mL of acetone, then add 6.83 μL of 2 M tartaric acid ethanol solution, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0577] X-ray powder diffraction analysis identified the product as tartrate crystal form I. The XRPD spectrum is shown in Figure 9, and the characteristic peak positions are listed in Table 9. Ion chromatography determined the tartrate content to be 22.73%. DSC spectroscopy showed endothermic peaks at 46.49, 121.48, 167.81, and 198.79 °C. TGA spectroscopy showed a weight loss of 0.51% from 31 °C to 77 °C and a weight loss of 1.28% from 78 °C to 140 °C.

[0578] Table 9

[0579] Example 9-1: Preparation of tartrate crystal form I of compound 1

[0580] Add 6 mg of compound 1 to 0.2 mL of the solvent in Table 9-1, then add 6.83 μL of 2M tartaric acid ethanol solution, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product is tartrate crystal form I.

[0581] Table 9-1

[0582] Example 10: Preparation of maleate crystal form I of compound of formula 1

[0583] 100 mg of compound 1 was added to 2 mL of ethanol, 25 mg of maleic acid solid was added, the mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product.

[0584] X-ray powder diffraction analysis identified the product as maleate crystal form I. The XRPD spectrum is shown in Figure 10, and the characteristic peak positions are listed in Table 10. Ion chromatography determined the maleic acid content to be 19.83%. The DSC spectrum showed an endothermic peak at 193.23℃. The TGA spectrum showed a weight loss of 0.32% from 30℃ to 80℃ and a weight loss of 4.83% from 80℃ to 261℃.

[0585] DVS testing showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample's moisture absorption weight gain was approximately 3.20%; under accelerated testing conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 3.54%; and under extreme conditions (90% RH), the moisture absorption weight gain was approximately 4.57%. Furthermore, retesting of the crystal form after DVS testing showed no change in crystal form.

[0586] Table 10

[0587] Example 11: Preparation of maleate crystal form II of compound of formula 1

[0588] Compound of Formula 1 (20 mg, 43.15 μmol) was added to methanol (0.5 mL), maleic acid (5 mg, 43.15 μmol) was added, and stirring was carried out without precipitation. Isopropyl ether (3 mL) was added, and stirring was continued for 24 h. The mixture was filtered, and the filter cake was collected and dried under vacuum to obtain the product (20 mg).

[0589] X-ray powder diffraction analysis determined that the crystal form was maleate crystal form II. The X-ray powder diffraction pattern is shown in Figure 11, and the positions of its characteristic peaks are shown in Table 11.

[0590] The DSC spectrum shows that the endothermic peaks are at 80.78℃ and 158.29℃. The TGA spectrum shows a weight loss of 2.29% between 30℃ and 65℃.

[0591] through 1 ¹H NMR analysis showed that the salt ratio of the compound to maleic acid was 1:1. The NMR data are as follows:

[0592] 1 H NMR (500MHz, DMSO): δ12.90(s,1H),8.33(d,4H),8.18(d,1H),7.90(d,1H),7.59(d,1H),7 .49(dd,1H),6.02(s,2H),5.00–4.90(m,2H),4.46(d,1H),4.40(d,1H),2.29–2.12(m,4H).

[0593] Table 11

[0594] Example 12: Preparation of maleate crystal form III of compound 1

[0595] Compound of Formula 1 (60 mg, 129.46 μmol) was added to isopropanol (6 mL), maleic acid (15 mg, 129.46 μmol) was added, and after stirring until dissolved, a solid precipitated. Stirring was continued for 24 h, and the mixture was filtered. The filter cake was collected and dried under vacuum to obtain the product (50 mg).

[0596] X-ray powder diffraction analysis determined that the crystal form was maleate crystal form III. The X-ray powder diffraction pattern is shown in Figure 12, and the positions of its characteristic peaks are shown in Table 12.

[0597] The DSC spectrum shows that the endothermic peaks are at 155.76℃ and 163.94℃. The TGA spectrum shows a weight loss of 2.11% between 30℃ and 80℃.

[0598] through 1 ¹H NMR analysis showed that the salt ratio of compound 1 to maleic acid was 1:1. The NMR data are as follows:

[0599] 1 H NMR (500MHz, DMSO): δ12.89(s,1H),8.34(d,4H),8.18(d,1H),7.89(s,1H),7.58(d,1H) ,7.49(dd,1H),6.04(s,2H),4.94(dt,2H),4.46(d,1H),4.40(d,1H),2.29–2.13(m,4H).

[0600] Table 12

[0601] Example 13: Preparation of maleate crystal form IV of compound of formula 1

[0602] Compound of Formula 1 (20 mg, 43.15 μmol) was added to isopropyl acetate (1 mL), maleic acid (5 mg, 43.15 μmol) was added, the white suspension was stirred, and stirring was continued for 24 h. The mixture was filtered, the filter cake was collected and dried under vacuum to obtain the product (20 mg).

[0603] X-ray powder diffraction analysis determined that the crystal form was maleate crystal form IV. The X-ray powder diffraction pattern is shown in Figure 13, and the positions of its characteristic peaks are shown in Table 13.

[0604] The DSC spectrum shows endothermic peaks at 87.95℃, 167.06℃, and 175.42℃. The TGA spectrum shows a weight loss of 1.48% between 30℃ and 80℃.

[0605] through 1 ¹H NMR analysis showed that the salt ratio of compound 1 to maleic acid was 1:1. The NMR data are as follows:

[0606] 1 H NMR (500MHz, DMSO): δ12.89(s,1H),8.33(s,1H),8.28(s,3H),8.18(d,1H),7.89(d,1H),7 .59(d,1H),7.49(dd,1H),6.02(s,2H),5.00–4.92(m,2H),4.42(q,2H),2.29–2.12(m,4H).

[0607] Table 13

[0608] Example 14: Preparation of maleate crystal form V of compound of formula 1

[0609] Compound of Formula 1 (816 mg, 1.77 mol) was added to ethanol (16 mL) to form a suspension. Maleic acid (206 mg, 1.77 mmol) was added, and the suspension was stirred for 20 h. The mixture was filtered, and the filter cake was collected and dried under vacuum to obtain the product (800 mg).

[0610] X-ray powder diffraction analysis determined that the crystal form was maleate crystal form V. The X-ray powder diffraction pattern is shown in Figure 14, and the positions of its characteristic peaks are shown in Table 14.

[0611] The DSC spectrum shows endothermic peaks at 89.31℃, 157.45℃, and 172.77℃. The TGA spectrum shows a weight loss of 2.77% between 30℃ and 140℃.

[0612] through 1 ¹H NMR analysis showed that the salt ratio of compound 1 to maleic acid was 1:1. The NMR data are as follows:

[0613] 1 H NMR (500MHz, DMSO): δ12.89(s,1H),8.33(s,1H),8.30(s,3H),8.18(d,1H),7.89(d,1H),7.58(d, 1H),7.50(dd,1H),6.02(s,2H),5.00–4.89(m,2H),4.45(d,1H),4.39(d,1H),2.29–2.12(m,4H).

[0614] Table 14

[0615] Example 15: Preparation of maleate crystal form VI of compound 1

[0616] Compound of Formula 1 (808 mg, 1.75 mmol) was added to acetonitrile (60 mL) to form a suspension. Maleic acid (211.4 mg, 1.82 mmol, dissolved in 10 mL of acetonitrile and added dropwise to the reaction solution) was then added. The suspension was stirred for 20 h, filtered, and the filter cake was collected and dried under vacuum to obtain the product (900 mg).

[0617] X-ray powder diffraction analysis determined that the crystal form was maleate crystal form VI. The X-ray powder diffraction pattern is shown in Figure 15, and the positions of its characteristic peaks are shown in Table 15.

[0618] The DSC spectrum shows that the endothermic peaks are at 76.11℃ and 166.28℃. The TGA spectrum shows a weight loss of 3.26% between 30℃ and 140℃.

[0619] through 1 ¹H NMR analysis showed that the salt ratio of compound 1 to maleic acid was 1:1. The NMR data are as follows:

[0620] 1H NMR (500MHz, DMSO): δ12.89(s,1H),8.34(d,4H),8.18(d,1H),7.89(s,1H),7.58(d,1H),7 .49(d,1H),6.03(s,2H),5.00–4.89(m,2H),4.46(d,1H),4.40(d,1H),2.29–2.13(m,4H).

[0621] Table 15

[0622] Example 16: Preparation of p-toluenesulfonate crystal form I of compound 1

[0623] Add 6 mg of compound 1 to 0.2 mL of ethyl acetate, then add 6.83 μL of 2 M p-toluenesulfonic acid ethanol solution, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0624] X-ray powder diffraction analysis identified the product as p-toluenesulfonate crystal form I. The XRPD spectrum is shown in Figure 16, and the characteristic peak positions are listed in Table 16. Ion chromatography analysis revealed a p-toluenesulfonic acid content of 33.12%. DSC spectroscopy showed endothermic peaks at 186.15 and 222.14 °C. TGA spectroscopy showed a weight loss of 0.21% from 31 °C to 140 °C.

[0625] Table 16

[0626] Example 17: Preparation of p-toluenesulfonate crystal form II of compound 1

[0627] Add 6 mg of compound 1 to 0.2 mL of acetone, then add 6.83 μL of 2 M p-toluenesulfonic acid ethanol solution, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0628] X-ray powder diffraction analysis identified the product as p-toluenesulfonate crystal form II. The XRPD spectrum is shown in Figure 17, and the characteristic peak positions are listed in Table 17. Ion chromatography determined the p-toluenesulfonic acid content to be 24.41%. DSC spectroscopy showed endothermic peaks at 159.49 and 252.15 °C. TGA spectroscopy showed a weight loss of 0.57% from 31 °C to 200 °C.

[0629] Table 17

[0630] Example 18: Preparation of p-toluenesulfonate crystal form III of compound 1

[0631] Add 6 mg of compound 1 to 0.2 mL of ethanol, then add 6.83 μL of 2 M p-toluenesulfonic acid ethanol solution, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0632] X-ray powder diffraction analysis identified the product as p-toluenesulfonate crystal form III. The XRPD spectrum is shown in Figure 18, and the characteristic peak positions are listed in Table 18. NMR analysis confirmed a 1:1 ratio of compound 1 to the acid ligand. DSC analysis showed endothermic peaks at 65.04, 215.89, 279.56, 295.70, and 326.66 °C, and an exothermic peak at 236.93 °C. TGA analysis showed no significant weight loss.

[0633] Table 18

[0634] Example 19: Preparation of p-toluenesulfonate crystal form IV of compound 1

[0635] The product was obtained by heating compound p-toluenesulfonate III of Formula 1 to 260°C.

[0636] X-ray powder diffraction analysis determined the product to be p-toluenesulfonate crystal form IV. The XRPD spectrum is shown in Figure 19, and the positions of its characteristic peaks are shown in Table 19.

[0637] Table 19

[0638] Example 20: Preparation of fumarate crystal form I of compound formula 1

[0639] 100 mg of compound 1 was added to 2 mL of ethanol, 25 mg of fumaric acid solid was added, the mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product.

[0640] X-ray powder diffraction analysis identified the product as fumarate crystal form I. The XRPD spectrum is shown in Figure 20, and the characteristic peak positions are listed in Table 20. Ion chromatography determined the fumaric acid content to be 19.90%. The DSC spectrum showed an endothermic peak at 247.23℃. The TGA spectrum showed no significant weight loss between 31℃ and 81℃.

[0641] DVS testing showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample's moisture absorption weight gain was approximately 0.61%; under accelerated testing conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 0.75%; and under extreme conditions (90% RH), the moisture absorption weight gain was approximately 1.10%. Furthermore, the crystal form remained unchanged after DVS testing and subsequent retesting.

[0642] Table 20

[0643] Example 20-1: Preparation of fumarate crystal form I of compound formula 1

[0644] 100 mg of compound of formula 1 was added to 2 mL of the solvent in Table 20-1, followed by 25 mg of solid fumaric acid. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis confirmed that the product was fumarate crystal form I.

[0645] Table 20-1

[0646] Example 21: Preparation of Succinate Crystal Form I of Compound Formula 1

[0647] Add 6 mg of compound 1 to 0.2 mL of ethyl acetate, add 1.6 mg of succinic acid solid, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0648] X-ray powder diffraction analysis identified the product as succinate crystal form I. The XRPD spectrum is shown in Figure 21, and the positions of its characteristic peaks are listed in Table 21. Ion chromatography determined the succinic acid content to be 28.15%. DSC spectroscopy showed endothermic peaks at 65.32, 140.15, 175.81, and 336.78 °C, and an exothermic peak at 272.16 °C. TGA spectroscopy showed a weight loss of 1.56% from 32 °C to 120 °C and a weight loss of 6.03% from 120 °C to 260 °C.

[0649] Table 21

[0650] Example 22: Preparation of Succinate Crystal Form II of Compound Formula 1

[0651] Add 6 mg of compound 1 to 0.2 mL of tetrahydrofuran, add 3.2 mg of succinic acid solid, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0652] X-ray powder diffraction analysis identified the product as succinate crystal form II. The XRPD spectrum is shown in Figure 22, and the characteristic peak positions are listed in Table 22. Ion chromatography analysis revealed a succinic acid content of 31.18%. DSC spectroscopy showed endothermic peaks at 176.32 and 339.24 °C, and an exothermic peak at 258.88 °C. TGA spectroscopy showed a weight loss of 1.69% from 31 °C to 140 °C and a weight loss of 21.12% from 141 °C to 280 °C.

[0653] Table 22

[0654] Example 22-1: Preparation of Succinate Crystal Form II of Compound Formula 1

[0655] 6 mg of compound of formula 1 was added to 0.2 mL of acetone, followed by 3.2 mg of succinic acid solid. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was succinate crystal form II.

[0656] Example 23: Preparation of benzoate crystal form I of compound 1

[0657] 100 mg of compound 1 was added to 2 mL of ethanol, followed by 113.8 μL of 2M benzoic acid ethanol solution. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product.

[0658] X-ray powder diffraction analysis identified the product as benzoate crystal form I. The XRPD spectrum is shown in Figure 23, and the characteristic peak positions are listed in Table 23. Ion chromatography analysis revealed a benzoate content of 21.36%. DSC spectroscopy showed endothermic peaks at 184.21 and 226.93 °C, and an exothermic peak at 187.73 °C. TGA spectroscopy showed no significant weight loss between 30 °C and 120 °C, and a weight loss of 17.95% between 120 °C and 210 °C.

[0659] DVS testing showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample's moisture absorption weight gain was approximately 0.32%; under accelerated testing conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 0.45%; and under extreme conditions (90% RH), the moisture absorption weight gain was approximately 0.79%. Furthermore, retesting of the crystal form after DVS testing showed no change in crystal form.

[0660] Table 23

[0661] Example 24: Preparation of benzoate form II of compound 1

[0662] Add 6 mg of compound 1 to 0.2 mL of tetrahydrofuran, then add 6.83 μL of 2M benzoic acid ethanol solution, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0663] X-ray powder diffraction analysis identified the product as benzoate crystal form II. The XRPD spectrum is shown in Figure 24, and the characteristic peak positions are listed in Table 24. Ion chromatography analysis revealed a benzoate content of 22.86%. DSC spectroscopy showed endothermic peaks at 153.00 and 223.65 °C, and an exothermic peak at 181.37 °C. TGA spectroscopy showed no significant weight loss between 31 °C and 80 °C, an 8.17% weight loss between 80 °C and 160 °C, and a 9.23% weight loss between 160 °C and 261 °C.

[0664] Table 24

[0665] Example 25: Preparation of benzoate crystal form III of compound 1

[0666] 100 mg of compound 1 was added to 2 mL of ethanol, followed by 113.8 μL of 2M benzoic acid ethanol solution. The mixture was stirred to induce crystallization, yielding a wet sample.

[0667] X-ray powder diffraction analysis determined the product to be benzoate crystal form III. The XRPD spectrum is shown in Figure 25, and the positions of its characteristic peaks are shown in Table 25.

[0668] Table 25

[0669] Example 26: Preparation of benzoate form IV of Formula 1

[0670] The benzoate crystal form I of compound formula 1 was heated to 190°C.

[0671] X-ray powder diffraction analysis determined the product to be benzoate crystal form IV. The XRPD spectrum is shown in Figure 26, and the positions of its characteristic peaks are shown in Table 26.

[0672] Table 26

[0673] Example 26-1: Preparation of benzoate form IV of compound 1

[0674] The product of compound benzoate II of Formula 1 was heated to 170°C and detected by X-ray powder diffraction as benzoate IV.

[0675] Example 26-2: Preparation of benzoate form IV of compound 1

[0676] The product of compound benzoate II of Formula 1 was heated to 195°C and detected by X-ray powder diffraction as benzoate IV.

[0677] Example 27: Preparation of Hypopurate Crystal Form I of Compound Formula 1

[0678] 100 mg of compound 1 was added to 2 mL of ethanol, followed by 41.3 mg of solid hippuric acid. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product.

[0679] X-ray powder diffraction (XRPD) analysis identified the product as hippurate crystal form I. The XRPD spectrum is shown in Figure 27, and the positions of its characteristic peaks are listed in Table 27. NMR analysis confirmed a 1:1 ratio of compound I to the acid ligand. DSC analysis showed an endothermic peak at 210.11℃. TGA analysis showed a weight loss of 0.55% from 32℃ to 102℃ and a weight loss of 4.43% from 102℃ to 248℃.

[0680] Table 27

[0681] Example 27-1: Preparation of Hydrupate Crystal Form I of Compound Formula 1

[0682] 100 mg of compound 1 was added to 2 mL of the solvent in Table 27-1, followed by 41.3 mg of solid hippuric acid. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis confirmed that the product was hippurate crystal form I.

[0683] Table 27-1

[0684] Example 28: Preparation of Hydrupate Crystal Form II of Compound Formula 1

[0685] Compound of Formula 1 (800 mg, 1.73 mmol) was added to acetonitrile (60 mL) to form a suspension. Hippuric acid (323.0 mg, 1.80 μmol, dissolved in 10 mL of acetonitrile and added dropwise to the reaction solution) was added to form a paste. The mixture was stirred for 20 h, filtered, and the mixture was gel-like. The mixture was washed with acetonitrile (1 mL), and the filter cake was collected and dried under vacuum to obtain the product (800 mg).

[0686] X-ray powder diffraction analysis determined that the crystal form was defined as hippurate crystal form II. The X-ray powder diffraction pattern is shown in Figure 28, and the positions of its characteristic peaks are shown in Table 28.

[0687] The DSC spectrum shows endothermic peaks at 86.8℃, 153.62℃, and 204.98℃. The TGA spectrum shows a weight loss of 0.85% between 30℃ and 70℃, and a weight loss of 1.29% between 70℃ and 185℃.

[0688] through 1 ¹H NMR analysis showed that the salt ratio of compound 1 to hippuric acid was 1:1. The NMR data are as follows:

[0689] 1 H NMR (500MHz, DMSO): δ12.54(s,1H),8.60(t,1H),8.27(s,1H),8.18(d,1H),7.89–7.83(m,2H),7.75(d,1H),7 .70(dd,1H),7.62–7.51(m,2H),7.48(t,2H),4.99–4.89(m,2H),3.92(s,2H),3.84(d,2H),2.29–2.12(m,4H).

[0690] Table 28

[0691] Example 29: Preparation of Mandelate Crystal Form I of Compound Formula 1

[0692] Add 6 mg of compound 1 to 0.2 mL of ethanol, add 2.1 mg of S-mandelic acid solid, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0693] X-ray powder diffraction analysis identified the product as mandelate crystal form I. The XRPD spectrum is shown in Figure 29, and the characteristic peak positions are listed in Table 29. NMR analysis confirmed a 1:1 ratio of compound I to the acid ligand. DSC spectra showed endothermic peaks at 168.13, 175.82, and 200.82 °C. TGA spectra showed a weight loss of 2.29% from 30 °C to 120 °C and a weight loss of 7.00% from 120 °C to 260 °C.

[0694] Table 29

[0695] Example 29-1: Preparation of Mandelate Crystal Form I of Compound Formula 1

[0696] 6 mg of compound of formula 1 was added to 0.2 mL of the solvent in Table 29-1, followed by 2.1 mg of solid S-mandelic acid. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis confirmed that the product was mandelic acid salt crystal form I.

[0697] Table 29-1

[0698] Example 30: Preparation of Acetate Crystal Form I of Compound Formula 1

[0699] Add 6 mg of compound 1 to 0.2 mL of ethyl acetate, then add 6.83 μL of 2 M acetic acid-ethanol solution, stir to induce crystallization, centrifuge, collect the solid and dry under vacuum to obtain the product.

[0700] X-ray powder diffraction analysis identified the product as acetate crystal form I. The XRPD spectrum is shown in Figure 30, and the characteristic peak positions are listed in Table 30. Ion chromatography determined the acetate content to be 13.65%. DSC spectroscopy showed endothermic peaks at 49.16, 130.81, 192.82, and 236.47 °C. TGA spectroscopy showed a weight loss of 0.46% from 30 °C to 80 °C and a weight loss of 6.59% from 80 °C to 179 °C.

[0701] Table 30

[0702] Example 31: Preparation of Malate Crystal Form I of Compound Formula 1

[0703] Add 6 mg of compound 1 to 0.2 mL of tetrahydrofuran, then add 6.83 μL of 2 M malic acid ethanol solution, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0704] X-ray powder diffraction analysis identified the product as malate crystal form I, and its XRPD spectrum is shown in Figure 31. The positions of its characteristic peaks are shown in Table 31. Ion chromatography analysis revealed a malate content of 27.88%.

[0705] Table 31

[0706] Example 32: Preparation of citrate crystal form I of compound 1

[0707] Compound of Formula 1 (100 mg, 215.8 μmol) was added to ethanol (4 mL) to form a white suspension. Citric acid (41.45 mg, 215.8 μmol, dissolved in 1 mL of ethanol and added dropwise to the reaction solution) was added to form a suspension. The mixture was stirred for 24 h, filtered, and the filter cake was collected and dried under vacuum to obtain the product.

[0708] X-ray powder diffraction analysis determined the product to be citrate crystal form I, and the X-ray powder diffraction pattern is shown in Figure 32.

[0709] The DSC spectrum shows endothermic peaks at 87.45℃, 166.08℃, and 191.41℃. The TGA spectrum shows a weight loss of 1.49% between 30℃ and 80℃, and a weight loss of 5.42% between 100℃ and 190℃.

[0710] ¹H NMR analysis showed that the salt ratio of compound 1 (formula 1) to citric acid was 1:0.4. The NMR data are as follows:

[0711] 1 H NMR (500MHz, CD3OD): δ8.21(d,1H),8.16(s,1H),7.84(s,1H),7.55(d,1H),7.33(d,1H),4.40(q,2H),2.81(d,1H),2.73(d,1H),2.35–2.17(m,4H).

[0712] Table 32

[0713] Example 33: Preparation of Hydrobromide Crystal Form I of Compound Formula 1

[0714] Compound of Formula 1 (20 mg, 43.15 μmol) was added to ethanol (1 mL), followed by 40% hydrobromic acid (17.24 mg, 43.15 μmol). After stirring until dissolved, a solid precipitated. Stirring was continued for 24 h. The mixture was then filtered, and the filter cake was collected and dried under vacuum to obtain the product.

[0715] X-ray powder diffraction analysis determined that the crystal form was hydrobromide crystal form I, and the X-ray powder diffraction pattern is shown in Figure 33.

[0716] Table 33

[0717] Example 34: Preparation of saccharin eutectic A of Formula 1

[0718] 100 mg of compound 1 was added to 2 mL of ethanol, followed by 58.3 mg of saccharin solid. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product.

[0719] X-ray powder diffraction analysis identified the product as saccharin eutectic A. The XRPD spectrum is shown in Figure 34, and the positions of its characteristic peaks are listed in Table 34. NMR analysis confirmed a 1:1 ratio of compound 1 to ligand. DSC analysis showed an endothermic peak at 265.05℃. TGA analysis showed a weight loss of 0.59% from 31℃ to 177℃.

[0720] Table 34

[0721] Example 35: Preparation of Saccharin Eucrystal B of Formula 1

[0722] 100 mg of compound 1 was added to 2 mL of ethyl acetate, followed by 58.3 mg of saccharin solid. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product.

[0723] X-ray powder diffraction analysis identified the product as saccharin eutectic B. The XRPD spectrum is shown in Figure 35, and the positions of its characteristic peaks are listed in Table 35. NMR analysis confirmed a 1:1 ratio of compound 1 to ligand. DSC spectra showed endothermic peaks at 48.16, 127.17, and 210.83 °C. TGA spectra showed a weight loss of 2.59% from 32 °C to 88 °C.

[0724] Table 35

[0725] Example 35-1: Preparation of Saccharin Eucrystal B of Formula 1

[0726] 100 mg of compound 1 was added to 2 mL of acetonitrile, followed by 58.3 mg of solid saccharin. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product. X-ray powder diffraction analysis confirmed that the product was saccharin eutectic B.

[0727] Example 36: Preparation of saccharin eutectic C of Formula 1

[0728] Add 6 mg of compound 1 to 0.2 mL of acetonitrile, add 4.6 mg of saccharin solid, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0729] X-ray powder diffraction analysis identified the product as saccharin eutectic C. The XRPD spectrum is shown in Figure 36, and the positions of its characteristic peaks are listed in Table 36. NMR analysis confirmed a 1:2 ratio of compound 1 to ligand. DSC spectra showed endothermic peaks at 121.67, 160.33, 203.49, and 239.33 °C. TGA spectra showed a weight loss of 2.62% between 30 °C and 120 °C, and a weight loss of 3.11% between 120 °C and 220 °C.

[0730] Table 36

[0731] Example 37: Preparation of the amorphous form of p-toluenesulfonate of Formula 1

[0732] Add 6 mg of compound 1 to 0.2 mL of tetrahydrofuran, then add 6.83 μL of 2 M p-toluenesulfonic acid ethanol solution, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0733] X-ray powder diffraction analysis revealed that the product was an amorphous p-toluenesulfonate. NMR analysis showed that the ratio of compound 1 to the acid ligand was 1:1.

[0734] Example 38: Preparation of the amorphous form of methanesulfonate of Formula 1

[0735] Add 6 mg of compound 1 to 0.2 mL of ethyl acetate, then add 6.83 μL of 2 M methanesulfonic acid ethanol solution, stir to induce crystallization, centrifuge, collect the solid and dry under vacuum to obtain the product.

[0736] X-ray powder diffraction analysis revealed that the product was an amorphous methanesulfonate. Ion chromatography analysis showed that its methanesulfonate content was 18.37%.

[0737] Example 39: Preparation of the amorphous form of tartrate salt of Formula 1

[0738] Add 6 mg of compound 1 to 0.2 mL of ethanol, then add 6.83 μL of 2 M tartaric acid ethanol solution, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0739] X-ray powder diffraction analysis revealed that the product was an amorphous tartrate. Ion chromatography analysis showed that its tartrate content was 22.62%.

[0740] Example 40: Preparation of the amorphous form of citrate of Formula 1 compound

[0741] Add 6 mg of compound 1 to 0.2 mL of tetrahydrofuran, then add 6.83 μL of 2M citric acid ethanol solution, stir to induce crystallization, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0742] X-ray powder diffraction analysis identified the product as an amorphous citrate. NMR analysis showed that the ratio of compound 1 to the acid ligand was 1:1.

[0743] Example 41: Preparation of Crystal Form II of Compound Hydrochloride of Formula 1

[0744] Weigh approximately 500 mg of the compound shown in Formula 1, add 25 mL of pH 1.6 hydrochloric acid aqueous solution, stir at 37°C for 14 hours, centrifuge and discard the supernatant to obtain the solid.

[0745] X-ray powder diffraction analysis determined the product to be hydrochloride crystal form II. The XRPD spectrum is shown in Figure 37, and the positions of its characteristic peaks are shown in Table 37.

[0746] Table 37

[0747] Example 42: Preparation of Crystal Form III of Compound Hydrochloride of Formula 1

[0748] Weigh about 500 mg of the compound shown in Formula 1, add 25 mL of pH 1.6 hydrochloric acid aqueous solution, stir at 37 °C for 20 hours, centrifuge and discard the supernatant, and dry under vacuum at 40 °C to obtain a solid.

[0749] X-ray powder diffraction analysis determined the product to be hydrochloride crystal form III. The XRPD spectrum is shown in Figure 38, and the positions of its characteristic peaks are shown in Table 38.

[0750] Table 38

[0751] Example 43: Stability Study of Influencing Factors

[0752] Hydrochloride crystal form I, sulfate crystal form II, fumarate crystal form I, maleate crystal form I, benzoate crystal form I, and saccharin eutectic A were laid out in an open container to investigate their stability under light (4500 Lux), high temperature (40℃, 60℃), and high humidity (RH 75%, RH 92.5%) conditions. The sampling and investigation period was one month. Table 43-1 shows the factors affecting the stability of hydrochloride crystal form I.

[0753] Conclusion: The chemical purity of hydrochloride crystal form I decreases under high temperature and light irradiation conditions, while its physicochemical stability is good under high humidity conditions.

[0754] Table 43-2 Factors Affecting the Stability of Sulfate Crystal Form II

[0755] Conclusion: The chemical purity of sulfate crystal form II decreases under high temperature and light irradiation conditions, but its chemical stability is good under high humidity conditions.

[0756] Table 43-3 Factors affecting the stability of fumarate crystal form I

[0757] Conclusion: The chemical purity of fumarate crystal form I decreases under high temperature and light conditions, but its physicochemical stability is good under high humidity conditions.

[0758] Table 43-4 Factors Affecting the Stability of Maleate Crystal Form I

[0759] Conclusion: Maleate crystal form I exhibits decreased chemical purity under high temperature and light conditions, but good physicochemical stability under high humidity conditions.

[0760] Table 43-5 Factors Affecting the Stability of Benzoate Crystal Form I

[0761] Conclusion: The chemical purity of benzoate crystal form I decreases under high temperature and light conditions, but its physicochemical stability is good under high humidity conditions.

[0762] Table 43-6 Factors Affecting the Stability of Saccharin Cocrystal Salt A

[0763] Conclusion: The chemical purity of saccharin eutectic A decreases under high temperature and light conditions, but its physicochemical stability is good under high humidity conditions.

[0764] Example 44: Long-term / Accelerated Stability

[0765] The stability of saccharin eutectic A, consisting of hydrochloride crystal form I, sulfate crystal forms II / III, fumarate crystal form I, maleate crystal form I, and benzoate crystal form I, was investigated under conditions of 25℃ / 60%RH and 40℃ / 75%RH.

[0766] Table 44-1 Long-term / accelerated stability of hydrochloride crystal form I

[0767] Conclusion: The chemical purity of hydrochloride crystal form I decreases under accelerated conditions, but its physicochemical stability is good under long-term conditions.

[0768] Table 44-2 Long-term / Accelerated Stability of Sulfate Crystal Form II

[0769] Conclusion: The chemical purity of sulfate crystal form II decreases under accelerated conditions, but its physicochemical stability is good under long-term conditions.

[0770] Table 44-3 Long-term / accelerated stability of sulfate crystal form III

[0771] Conclusion: The chemical purity of sulfate crystal form III decreases under accelerated conditions, but its physicochemical stability is good under long-term conditions.

[0772] Table 44-4 Long-term / Accelerated Stability of Fumarate Crystal Form I

[0773] Conclusion: The chemical purity of fumarate crystal form I decreases under accelerated conditions, but its physicochemical stability is good under long-term conditions.

[0774] Table 44-5 Long-term / Accelerated Stability of Maleate Crystal Form I

[0775] Conclusion: Maleate crystal form I exhibits decreased chemical purity under accelerated conditions but good physicochemical stability under long-term conditions.

[0776] Table 44-6 Long-term / Accelerated Stability of Benzoate Crystal Form I

[0777] Conclusion: Benzoate crystal form I exhibits decreased chemical purity under accelerated conditions but good physicochemical stability under long-term conditions.

[0778] Table 44-7 Long-term / Accelerated Stability of Saccharin Eucrystal A

[0779] Conclusion: The chemical purity of saccharin eutectic A decreases under accelerated conditions, but its physicochemical stability is good under long-term conditions.

Claims

1. A pharmaceutically acceptable salt of compound (M)-(2aS,8aR)-5-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-(methyl-d3)-1H-pyrazol-5-yl)-6-fluoro-1,2,2a,8a-tetrahydrobenzo[b]cyclobutano[e][1,4]dioxane-4-carboxynitrile, said pharmaceutically acceptable salt being selected from hydrochloride, sulfate, phosphate, tartrate, maleate, p-toluenesulfonate, fumarate, succinate, benzoate, hippurate, mandelate, acetate, malate, citrate, hydrobromide, and methanesulfonate.

2. The medicinal salt according to claim 1, characterized in that, The chemical ratio of the compound of Formula 1 to the acid is 3:1-1:3, preferably 2:1-1:2, and more preferably 1:1 or 1:

2.

3. The method for preparing a pharmaceutically acceptable salt according to claim 1 or 2, comprising the step of reacting the compound of formula 1 with an acid, wherein the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, maleic acid, p-toluenesulfonic acid, fumaric acid, succinic acid, benzoic acid, hippuric acid, mandelic acid, acetic acid, malic acid, citric acid, hydrobromic acid, and methanesulfonic acid.

4. A hydrochloride crystal form I of the compound shown in Formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 14.610, 20.080, 21.271, 22.324, and 24.621, preferably at 5.340, 14.610, 16.272, 20.080, 21.271, 22.324, 23.480, 24.621, and 25.346, and more preferably at 5.340, 10.302, 11.290, 14.610, 16.272, 20.080, 21.271, 22.324, 23.480, 24.621, 25.346, 27.371, and 29.

417.

5. The hydrochloride crystal form I according to claim 4, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 2.

6. A method for preparing hydrochloride crystal form I as described in claim 4 or 5, the method comprising: The compound of Formula 1 was added to solvent I, followed by the addition of hydrochloric acid ethanol solution and stirring. Solvent I was selected from ethyl acetate, ethanol, acetone, and tetrahydrofuran.

7. A sulfate crystal form II of the compound shown in Formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 5.952, 16.549, 19.003, 22.694, and 24.584, preferably at 5.952, 8.063, 10.135, 16.549, 19.003, 20.881, 22.694, 24.584, and 25.961, and more preferably at 5.952, 8.063, 10.135, 14.597, 16.549, 19.003, 19.825, 20.881, 22.694, 24.584, 25.961, and 27.

256.

8. The sulfate crystal form II according to claim 7, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 4.

9. A method for preparing sulfate crystal form II as described in claim 7 or 8, the method comprising: Compound of Formula 1 was added to ethyl acetate, followed by an aqueous solution of sulfuric acid, and stirred.

10. A sulfate crystal form III of the compound shown in Formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 5.321, 15.107, 18.754, 20.155, 23.589, and 24.174, preferably at 5.321, 9.253, 14.209, 15.107, 18.754, 20.155, 21.573, 23.589, 24.174, and 27.644, and more preferably at 5.321, 9.253, 14.209, 15.107, 16.132, 16.948, 17.853, 18.754, 20.155, 21.573, 23.589, 24.174, 27.644, and 28.

733.

11. The sulfate crystal form IⅠI according to claim 10, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 5.

12. A method for preparing sulfate crystal form I or II as described in claim 10 or 11, the method comprising: Compound of Formula 1 was added to ethanol, followed by an aqueous solution of sulfuric acid, and the mixture was stirred.

13. A maleate crystal form I of the compound shown in Formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 7.549, 14.615, 15.377, 24.328, and 24.608, preferably at 6.229, 7.549, 14.615, 15.377, 21.796, 24.328, 24.608, and 27.427, and more preferably at 4.917, 6.229, 7.549, 14.615, 15.377, 16.487, 16.854, 21.796, 24.328, 24.608, 25.473, and 27.

427.

14. The maleate crystal form I according to claim 13, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 10.

15. A method for preparing maleate crystal form I as described in claim 13 or 14, the method comprising: Compound of Formula 1 was added to ethanol, maleic acid was added, and the mixture was stirred.

16. A fumarate crystal form I of the compound shown in Formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 4.760, 14.588, and 19.450, preferably at 4.760, 11.938, 14.588, 19.450, and 21.705, and more preferably at 4.760, 9.204, 11.938, 14.588, 18.143, 19.450, 21.705, 25.258, and 28.

413.

17. The fumarate crystal form I according to claim 16, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 20.

18. A method for preparing fumarate crystal form I as described in claim 16 or 17, the method comprising: The compound of Formula 1 was added to solvent II, fumaric acid was added, and the mixture was stirred. Solvent II was selected from ethanol, acetone, and tetrahydrofuran.

19. A benzoate crystal form I of the compound shown in Formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 5.676, 11.524, 16.837, 17.189, and 23.016, preferably at 5.676, 11.524, 16.837, 17.189, 19.104, 20.647, 22.585, 23.016, and 27.186, and more preferably at 5.676, 8.921, 11.524, 13.931, 16.837, 17.189, 18.429, 19.104, 20.647, 22.585, 23.016, 27.186, and 27.

909.

20. The benzoate crystal form I according to claim 19, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 23.

21. A method for preparing benzoate crystal form I as described in claim 19 or 20, the method comprising: Compound of Formula 1 was added to ethanol, followed by a benzoic acid ethanol solution, and the mixture was stirred.

22. A cocrystal of the compound shown in Formula 1, wherein the ligands of the cocrystal are selected from saccharin, L-phenylalanine, L-tyrosine, L-tryptophan, L-histidine, L-aspartic acid, L-arginine, L-lysine and L-proline.

23. The eutectic of the compound of formula 1 according to claim 22, characterized in that, The chemical ratio of the compound of Formula 1 to the ligand is 2:1 to 1:2, preferably 1:1 or 1:

2.

24. A method for preparing a eutectic of a compound of formula 1 as described in claim 22 or 23, comprising the step of reacting the compound of formula 1 with a ligand selected from saccharin, L-phenylalanine, L-tyrosine, L-tryptophan, L-histidine, L-aspartic acid, L-arginine, L-lysine, and L-proline.

25. A saccharin eutectic A of the compound shown in Formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 16.700, 17.339, 20.409, 20.747, and 24.370, preferably at 11.520, 16.700, 17.339, 20.409, 20.747, 23.313, 24.370, and 26.464, and more preferably at 11.520, 14.798, 15.492, 16.700, 17.339, 20.409, 20.747, 23.313, 24.370, 26.464, and 28.

063.

26. The saccharin eutectic A of the compound of formula 1 according to claim 25, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 34.

27. A method for preparing saccharin eutectic A of the compound of Formula 1 as described in claim 25 or 26, the method comprising: Compound of Formula 1 was added to ethanol, saccharin was added, and the mixture was stirred.

28. The crystal form according to any one of claims 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, 25-26, wherein the 2θ angle error range is ±0.

20.

29. A pharmaceutical composition comprising a pharmaceutically acceptable salt as claimed in claim 1 or 2, or a eutectic as claimed in claim 22 or 23, or a crystal form as claimed in any one of claims 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, 25-26, and optionally a pharmaceutically acceptable excipient.

30. A method for preparing a pharmaceutical composition, comprising the following steps: The step of mixing the pharmaceutically acceptable salt of claim 1 or 2, or the eutectic of claim 22 or 23, or the crystal form of any one of claims 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, 25-26 with a pharmaceutically acceptable excipient.

31. Use of the pharmaceutically acceptable salt of claim 1 or 2, or the eutectic of claim 22 or 23, or the crystal form of any one of claims 4-5, 7-8, 10-11, 13-14, 16-17, 19-20, 25-26, or the pharmaceutical composition of claim 29 in the preparation of a medicament for the prevention and / or treatment of cancer.

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